Benzodiazepine analogs

ABSTRACT

Benzodiazepine analogs of the formula: ##STR1## are disclosed which are antagonists of gastrin and cholecystokinin (CCK).

CROSS-REFERENCE

This is a CIP of U.S. Ser. No. 741,972 filed June 10, 1985, nowabandoned which is a continuation in part of U.S. Ser. No. 705,272 filedFeb. 25, 1985, now abandoned, which in turn is a Continuation in part ofU.S. Ser. No. 624,854, filed June 26, 1984, now abandoned.

Starting materials for the compounds of Formula I are described inpatent application U.S. Ser. No. 942,131, filed Dec. 16, 1986, which isa continuation in part of U.S. Ser. No. 624,853, filed June 26, 1984,now abandoned entitled "Acylaminophenylketones and Amines", which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

Cholecystokinins (CCK) and gastrin are structurally-relatedneuropeptides which exist in gastrointestinal tissue and in the thecentral nervous system (see, V. Mutt, Gastrointestinal Hormones, G. B.J. Glass, Ed., Raven Press, N.Y., p. 169 and G. Nisson, ibid, p. 127).

Cholecystokinins include CCK-33, a neuropeptide of thirty-three aminoacids in its originally isolated form (see, Mutt and Jorpes, Biochem. J.125, 678 (1971)), its carboxylterminal octapeptide, CCK-8 (anaturally-occurring neuropeptide, also, and the minimum fully activesequence), and 39- and 12-amino acid forms, while gastrin occurs in 34-,17- and 14-amino acid forms, with the minimum active sequence being theC-terminal pentapeptide, Gly-Trp-Met-Asp-Phe-NH₂, which is the commonstructural element shared by both CCK and gastrin.

CCK's are believed to be physiological satiety hormones, therebypossibly playing an important role in appetite regulation (G. P. Smith,Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds, RavenPress, New York, 1984, p. 67), as well as also stimulating colonicmotility, gall bladder contraction, pancreatic enzyme secretion, andinhibiting gastric emptying. They reportedly co-exist with dopamine incertain mid-brain neurons and thus may also play a role in thefunctioning of dopaminergic systems in the brain, in addition to servingas neurotransmitters in their own right (see: A. J. Prange et al.,"Peptides in the Central Nervous System", Ann. Repts. Med. Chem. 17, 31,33 [1982] and references cited therein; J. A. Williams, Biomed. Res. 3107 [1982]); and J. E. Morley, Liee Sci. 30, 479, [1982]).

The primary role of gastrin, on the other hand, appears to bestimulation of the secretion of water and electrolytes from the stomach,and, as such, it is involved in control of gastric acid and pepsinsecretion. Other physiological effects of gastrin then include increasedmucosal blood flow and increased antral motility, with rat studieshaving shown that gastrin has a positive trophic effect on the gastricmucosa, as evidenced by increased DNA, RNA and protein synthesis.

Antagonists to CCK and to gastrin have been useful for preventing andtreating CCK-related and/or gastrin-related disorders of thegastrointestinal (GI) and central nervous (CNS) systems of animals,especially of humans. Just as there is some overlap in the biologicalactivities of CCK and gastrin, antagonists also tend to have affinityfor both receptors. In a practical sense, however, there is enoughselectivity to the different receptors that greater activity againstspecific CCK- or gastrin-related disorders can often also be identified.

Selective CCK antagonists are themselves useful in treating CCK-relateddisorders of the appetite regulatory systems of animals as well as inpotentiating and prolonging opiate-mediated analgesia, thus havingutility in the treatment of pain [see P. L. Faris et al., Science 226,1215 (1984)], while selective gastrin antagonists are useful in themodulation of CNS behavior, as a palliative for gastrointestinalneoplasms, and in the treatment and prevention of gastrin-relateddisorders of the gastrointestinal system in humans and animals, such aspeptic ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia andother conditions in which reduced gastrin activity is of therapeuticvalue.

Also, since CCK and gastrin also have trophic effects on certain tumors[K. Okyama, Hokkaido J. Med. Sci., 60, 206-216 (1985)], antagonists ofCCK and gastrin are useful in treating these tumors [see, R. D.Beauchamp et al., Ann. Surg., 202,303 (1985)].

Four distinct chemical classes of CCK-receptor antagonists have beenreported. The first class comprises derivatives of cyclic nucleotides,of which dibutyryl cyclic GMP has been shown to be the most potent bydetailed structure-function studies (see, N. Barlos et al., Am. J.Physiol., 242, G 161 (1982) and P. Robberecht et al., Mol., Pharmacol.,17, 268 (1980)).

The second class comprises peptide antagonists which are C-terminalfragments and analogs of CCK, of which both shorter(Boc-Met-Asp-Phe-NH₂, Met-Asp-Phe-NH₂), and longer (Cbz-Tyr(SO₃H)-Met-Gly-Trp-Met-Asp-NH₂) C-terminal fragments of CCK can function asCCK antagonists, according to recent structure-function studies (see, R.T. Jensen et al., Biochem. Biophys. Acta., 757, 250 (1983), and M.Spanarkel et al., J. Biol. Chem., 258, 6746 (1983)). The latter compoundwas recently reported to be a partial agonist [see, J. M. Howard et al.,Gastroenteroloqy 86(5) Part 2, 1118 (1984)].

Then, the third class of CCK-receptor antagonists comprises the aminoacid derivatives: Proglumide, a derivative of glutaramic acid, and theN-acyl tryptophans including para-chlorobenzoyl-L-tryptophan(benzotript), [see, W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A.,78, 6304 (1981), R. T. Jensen et al., Biochem. Biophys. Acta., 761, 269(1983)]. All of these compounds, however, are relatively weakantagonists of CCK (IC₅₀ : generally 10⁻⁴ M [although more potentanalogs of proglumide have been recently reported in F. Makovec et al.,Arzneim-Forsch Drug Res., 35 (II), 1048 (1985) and in German PatentApplication No. DE 3522506A1], but down to 10⁻⁶ M in the case ofpeptides), and the peptide CCK-antagonists have substantial stabilityand absorption problems.

In addition, a fourth class consists of improved CCK-antagonistscomprising a nonpeptide of novel structure from fermentation sources [R.S. L. Chang et al., Science, 230, 177-179 (1985)] and 3-substitutedbenzodiazepines based on this structure [published European PatentApplications 167 919, 167 920 and 169 392, B. E. Evans et al, Proc.Natl. Acad. Sci. U.S.A., 83, p. 4918-4922 (1986) and R. S. L. Chang etal, ibid, p. 4923-4926] have also been reported.

No really effective receptor antagonists of the in vivo effects ofgastrin have been reported (J. S. Morley, Gut Pept. Ulcer Proc.,Hiroshima Symp. 2nd, 1983, p. 1), and very weak in vitro antagonists,such as proglumide and certain peptides have been described [(J.Martinez, J. Med. Chem. 27, 1597 (1984)]. Recently, however,pseudopeptide analogs of tetragastrin have been reported to be moreeffective gastrin antagonists than previous agents [J. Martinez et al.,J. Med. Chem., 28, 1874-1879 (1985)].

The benzodiazepine (BZD) structure class, which has been widelyexploited as therapeutic agents, especially as central nervous system(CNS) drugs, such as anxiolytics, and which exhibits strong binding to"benzodiazepine receptors" in vitro, has not in the past been reportedto bind to CCK or gastrin receptors. Benzodiazepines have been shown toantagonize CCK-induced activation of rat hippocampal neurones but thiseffect is mediated by the benzodiazepine receptor, not the CCK receptor[see J. Bradwejn et al., Nature, 312, 363 (1984)]. Of these reportedBZD's, additionally, the large majority do not contain substituentsattached to the 3-position of the seven membered ring, as it is wellknown in the art that 3-substituents result in decreasing anxiolyticactivity, especially as these substituents increase in size.

It was, therefore, an object of this invention to identify substanceswhich more effectively antagonize the function of cholecystokinins andgastrin in disease states in animals, preferably mammals, especially inhumans. It was another object of this invention to prepare novelcompounds which more selectively inhibit cholecystokinins or inhibitgastrin. It was still another object of this invention to develop amethod of antagonizing the functions of cholecystokinin and gastrin indisease states in mammals. It is also an object of this invention todevelop a method of preventing or treating disorders of thegastrointestinal, central nervous and appetite regulatory systems ofmammals, especially of humans, or of increasing food intake of animals.

SUMMARY OF THE INVENTION

It has now been found that compounds of Formula I are antagonists ofgastrin and cholecystokinin (CCK) and bind to the gastrin and CCKreceptors. These compounds are useful in the treatment and prevention ofCCK-related disorders of the gastrointestinal, central nervous andappetite regulatory systems of animals, preferably mammals andespecially humans. They are also useful in the treatment and preventionof gastrin related disorders, gastrointestinal ulcers, Zollinger-Ellisonsyndrome, antral G cell hyperplasia, and other conditions in whichreduced gastrin activity is of therapeutic value.

Also within the invention are those compounds of Formula I that arenovel.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I are useful in a method of antagonizing thebinding of cholecystokinins to cholecystokinin receptors or antagonizingthe binding of gastrin to gastrin receptors which comprises contactingsaid cholecystokinin receptors or said gastrin receptors, respectively,with a compound represented by the formula: ##STR2## wherein R¹ is H, C₁-C₆ linear or branched alkyl, loweralkenyl, lower alkynyl, --X¹² COOR⁶,-x¹¹ cycloloweralkyl, --X¹² NR⁴ R⁵,--X¹² CONR⁴ R⁵, --X¹² CN, or --X¹¹CX₃ ¹⁰ ;

R² is H, loweralkyl, substituted or unsubstituted phenyl (wherein thesubstitutents may be 1 or 2 of halo, loweralkyl, loweralkoxy,loweralkylthio, carboxyl, carboxyloweralkyl, nitro, --CF₃, or hydroxy),2-, 3-, 4-pyridyl, ##STR3## R⁴ and R⁵ are independently R⁶ or incombination with the N of the NR⁴ R⁵ group form an unsubstituted or monoor disubstituted, saturated or unsaturated, 4-7 membered hetrocyclicring or benzofused 4-7 membered heterocyclic ring, or said heterocyclicring or said benzofused heterocyclic ring which further comprises asecond heteroatom selected from O and NCH₃ and the substituent(s) is/areindependently selected from C₁₋₄ alkyl;

R⁶ is H, loweralkyl, cycloloweralkyl, substituted or unsubstitutedphenyl, or substituted or unsubstituted phenylloweralkyl wherein thephenyl or phenyloweralkyl substituents may be 1 or 2 of halo,loweralkyl, loweralkoxy, nitro, or CF₃ ;

R⁷ and R_(a) ⁷ are independently α- or β-naphthyl, substituted orunsubstituted phenyl (wherein the substituents may be 1 or 2 of halo--NO₂, --OH, --X¹¹ NR⁴ R⁵, loweralkyl, CF₃, CN, SCF₃, C.tbd.CH, CH₂SCF₃, ##STR4## OCHF₂, SH, SPh, PO₃ H-loweralkoxy, or loweralkylthio,COOH); 2-, 3-, 4- pyridyl, ##STR5## R⁸ is H, loweralkyl,cycloloweralkyl, --X¹² CONH₂, --X¹² COOR⁶, --X¹² -cycloloweralkyl, --X¹²NR⁴ R⁵, ##STR6## R⁹ and R¹⁰ are independently H, --OH, or --CH₃ ; R¹¹and R¹² are independently lowralkyl or cycloloweralkyl;

R¹³ is H, loweralkyl, acyl, O, or cycloloweralkyl;

R¹⁴ is loweralkyl or phenylloweralkyl;

R¹⁵ is H, loweralkyl, ##STR7## or --NH₂ ; R¹⁸ is H, loweralkyl, or acyl;

p is 0 when its adjacent--is unsaturated and 1 when its adjacent--issaturated except that when R¹³ is O, p=1 and--is unsaturated;

q is 0-4;

r is 1 or 2;

X¹ is H, --NO₂, CF₃, CN, OH, loweralkyl, halo, loweralkylthio,loweralkoxy, --X¹¹ COOR⁶, or --X¹¹ NR⁴ R⁵ ;

X² and X³ are independently H, --OH,--NO², halo, loweralkylthio,loweralkyl, or loweralkoxy;

X⁴ is S, O, CH₂, or NR¹⁸ or NR⁸ ;

X⁵ is H, CF₃, CN, --COOR⁶, NO₂, or halo;

X⁶ is O or HH;

X⁷ is O, S, HH, or NR¹⁵ with the proviso that X⁷ can be NR¹⁵ only whenR¹ is not H;

X⁸ is H, loweralkyl;

X⁹ and X_(a) ⁹ are independently NR¹⁸ or O;

X¹⁰ is F, Cl, or Br;

X¹¹ is absent or C₁₋₄ linear or branched alkylidene;

X¹² is C₁₋₄ linear or branched alkylidene;

--is a saturated or unsaturated bond

and the pharmaceutically acceptable salts thereof.

Also within the invention are the novel compounds of Formula II:##STR8## wherein R¹ is H, C₁ -C₆ linear or branched alkyl, loweralkenyl,lower alkynyl, --X¹² COOR⁶, --X¹¹ -cycloloweralkyl, --X¹² NR⁴ R⁵, --X¹²CONR⁴ R⁵, --X¹² CN, or --X¹¹ CX₃ ¹⁰ ;

R² is H, loweralkyl, substituted or unsubstituted phenyl (wherein thesubstitutents may be 1 or 2 of halo, loweralkyl, loweralkoxy,loweralkyllthio, carboxyl, carboxyloweralkyl, nitro, --CF₃, or hydroxy),2-, 3-, 4-pyridyl, ##STR9## with the proviso that R¹⁰ is not H or --CH₃when R³ is ##STR10## R⁴ and R⁵ are independently R⁶ or in combination R⁴and R⁵ are independently R⁶ or in combination with the N of the NR⁴ R⁵group form an unsubstituted or mono or disubstituted, saturated orunsaturated, 4-7 membered heterocyclic ring, or benzofused 4-7 memberedheterocyclic ring or said heterocyclic ring or said benzofusedheterocyclic ring which further comprises a second heteroatom selectedfrom O and NCH₃ and the substituent(s) is/are independently selectedfrom C₁₋₄ alkyl;

R⁶ is H, loweralkyl, cycloloweralkyl, substituted or unsubstitutedphenyl, or substituted or unsubstituted phenylloweralkyl wherein thephenyl or phenylloweralkyl substituents may be 1 or 2 of halo,loweralkyl, loweralkoxy, nitro, or CF₃ ;

R⁷ is α- or β-naphthyl, substituted or unsubstituted phenyl (wherein thesubstituents may be 1 to 2 of halo, --NO₂, --OH,--X¹¹ NR⁴ R⁵,loweralkyl, CF₃, CN, SCF₃, C.tbd.CH, CH₂ SCF₃, ##STR11## OCHF₂, SH, SPh,PO₃ H, loweralkoxy, loweralkylthio or COOH), 2-, 3-, 4- pyridyl,##STR12## R⁸ is H, loweralkyl, cycloloweralkyl, --X¹² CONH₂, --X¹²COOR⁶, --X¹² -cycloloweralkyl, --X¹² NR⁴ R⁵, ##STR13## R⁹ and R¹⁰ areindependently H, --OH, or --CH₃ ; R¹¹ and R¹² are independentlyloweralkyl or cycloloweralkyl;

R¹³ is H, loweralkyl, acyl, O, or cycloloweralkyl;

R¹⁴ is loweralkyl or phenylloweralkyl;

R¹⁵ is H, loweralkyl, ##STR14## or --NH₂ ; R¹⁶ is alpha or beta naphthylor 2-indolyl;

R¹⁸ is H or loweralkyl;

p is 0when its adjacent--is unsaturated and 1 when its adjacent--issaturated except that when R¹³ is O, p=1 and--unsaturated;

q is 0-4;

r is 1 or 2;

X¹ is H, --NO₂, CF₃ CN, OH, loweralkyl, halo, loweralkylthio,loweralkoxy, --X¹¹ COOR⁶, or --X¹¹ NR⁴ R⁵ ;

X² and X³ are independently H, --OH, --NO₂, halo, loweralkylthio,loweralkyl, or loweralkoxy;

X⁴ is S, O, CH₂, or NR⁸ ;

X⁵ is H, CF₃, CN, --COOR⁶, NO₂, or halo;

X⁶ is O or HH;

X⁷ is O, S, HH, or NR¹⁵ with the proviso that X⁷ can be NR¹⁵ only whenR¹ is not H;

X⁸ is H, loweralkyl;

X⁹ and X_(a) ⁹ are independently NR¹⁸, O;

X¹⁰ is F, Cl, or Br;

X¹¹ is absent or C₁₋₄ linear or branched alkylidene;

X¹² is C₁₋₄ linear or branched alkylidene;

--is a saturated or unsaturated bond; with the proviso that when X_(r) ¹is Cl in the seven position, R¹ is H and R² is unsubstituted phenyl,then R³ is not NHCO(CH₂)₂ C₆ H₅ or NHCOC₆ H₅ ;

and the pharmaceutically acceptable salts thereof.

As used herein, the definition of each expression, e.g. m, n, p,loweralkyl, etc., when it occurs more than once in any structure, isintended to be independent of its definiton elsewhere in the samestructure. Thus, the ring fragment ##STR15## since each p isindependently 1 or 0, represents the three structures ##STR16## whenR¹³, is not 0.

In the compounds of Formula I, the preferred stereochemistry for CCKantagonism relates to D-tryptophan, where C² and N⁴ of Formula Icorrespond to the carbonyl carbon and α-amino N of D-tryptophan and R³occupies the position of the indolylmethyl side chain.

In the compounds of Formula I, the preferred stereochemistry for gastrinantagonism can be either D or L depending on the nature of R³. Forexample, when R³ =X¹¹ R⁷ or ##STR17## the preferred stereochemistrycorresponds to D-tryptophan, as above. When ##STR18## the preferredstereochemistry corresponds to L-tryptophan.

As used herein, halo is F, Cl, Br or I; loweralkyl is 1-7 carbonstraight or branched chain alkyl and includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and t-butyl, pentyl, hexyl, and heptyl; inloweralkoxy and loweralkylthio, the alkyl portion is loweralkyl aspreviously defined; cycloloweralkyl is cycloalkyl of 3-7 carbons;loweralkenyl is 1-5 carbon straight or branched chain alkenyl; acyl isformyl, acetyl, propionyl, benzoyl or butyryl; loweralkynyl is 1-5carbon straight or branched chain alkynyl.

The pharmaceutically acceptable salts of the compounds of Formulas Iinclude the conventional non-toxic salts or the quarternary ammoniumsalts of the compounds of Formula I formed, e.g., from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula I which contain a basic oracidic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formula I are alsoreadily prepared by conventional procedures such as treating an acid ofFormula I with an appropriate amount of a base, such as an alkali oralkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium,or magnesium, or an organic base such as an amine, e.g.,dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine,benzylamine and the like, or a quaternary ammonium hydroxide such astetramethylammonium hydroxide and the like.

An embodiment of this invention is the preparation of compounds ofFormula II.

The ability of the compounds of Formula I to antagonize CCK and gastrinmakes these compounds useful as pharmaceutical agents for mammals,especially for humans, for the treatment and prevention of disorderswherein CCK and/or gastrin may be involved. Examples of such diseasestates include gastrointestinal disorders, especially such as irritablebowel syndrome, gastroesophageal reflux disease or ulcers, excesspancreatic or gastric secretion, acute pancreatitis, or motilitydisorders; central nervous system disorders, caused by CCK interactionswith dopamine, such as neuroleptic disorders, tardive dyskinesia,Parkinson's disease, psychosis or Gilles de la Tourette Syndrome;disorders of appetite regulatory systems; Zollinger-Ellison syndrome,antral G cell hyperplasia, or pain (potentiation of opiate analgesia);as well as certain tumors of the lower esophagus, stomach, intestinesand colon.

The compounds of Formula I thereof, may be administered to a humansubject either alone or, preferably, in combination withpharmaceutically-acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including intravenous, intramuscular,intraperitoneal, subcutaneous and topical administration.

For oral use of an antagonist of CCK, according to this invention, theselected compounds may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

When a compound according to Formula I is used as an antagonist of CCKor gastrin in a human subject, the daily dosage will normally bedetermined by the prescribing physician with the dosage generallyvarying according to the age, weight, and response of the individualpatient, as well as the severitY of the patient's symptoms. However, inmost instances, an effective daily dosage will be in the range of fromabout 0.05 mg/kg to about 50 mg/kg of body weight, and preferably, offrom 0.5 mg/kg to about 20 mg/kg of body weight, administered in singleor divided doses. In some cases, however, it may be necessary to usedosages outside these limits.

In the treatment of irritable bowel syndrome, for instance, 0.1 to 10mg/kg of a CCK antagonist might be administered orally (p.o.), dividedinto two doses per day (b.i.d.). In treating delayed gastric emptying,the dosage range would probably be the same, although the drug might beadministered either intravenously (I.V.) or orally, with the I.V. doseprobably tending to be slightly lower due to better availability. Acutepancreatitis might be treated preferentially in an I.V. form, whereasspasm and/or reflex esophageal, chronic pancreatitis, post vagotomydiarrhea, anorexia or pain associated with biliary dyskinesia mightindicate p.o. form administration.

In the use of a gastrin antagonist as a tumor palliative forgastrointestinal neoplasms with gastrin receptors, as a modulator ofcentral nervous system activity, treatment of Zollinger-Ellisonsyndrome, or in the treatment of peptic ulcer disease, a dosage of 0.1to 10 mg/kg administered one-to-four times daily might be indicated.

Because these compounds antagonize the function of CCK in animals, theymay also be used as feed additives to increase the food intake ofanimals in daily dosage of approximately 0.05 to 50 mg/kg of bodyweight.

The compounds of Formula I are prepared according to the followingschemes. ##STR19## Where, in the 24 compound, R¹ and/or R⁸ is an ester[(X¹²)COO--C₁ -C₃ alkyl] moiety, this group can be conventionallyhydrolyzed to obtain the corresponding acid moiety or treated with NH₃to obtain the corresponding amide moiety. ##STR20##

2-Aminoarylketones 1, (Scheme I) preferably 2-amino-benzophenonescontaining various substituents in the aryl rings, preferably halosubstituents, are coupled to N-protected D-amino acids 2 (preferably,Boc-amino acids) using dicyclohexylcarbodiimide (DCC) or otherconventional peptide coupling reagent. The product 3 is N-deprotected bytreatment with acid, preferably anhydrous HCl in ethyl acetate, to givethe α-aminoacyl derivative 4 of the 2-aminoarylketone. Alternatively,this same product is obtained by treatment of the 2-aminoarylketone 1with the acid chloride hydrochloride 5 of the D-amino acid, which isprepared from the amino acid with PCl₅ -AcCl.

Treatment of this α-aminoacyl derivative 4 with base, preferably aqueoussodium hydroxide in methanol, gives the free base 6 which is cyclized tothe 3,5-disubstituted benzodiazepine 7 upon stirring in the methanolicbase for 2-120 hours, preferably 48 hours. Alternatively, the3,5-disubstituted benzodiazepine 7 is obtained by heating the2-aminoarylketone 1 with the ester 8, preferably methyl or ethyl, of theD-amino acid, preferably in refluxing pyridine, for 2-48 hours,preferably for 18 hours.

Alternatively (Scheme V), the ketones 1 may be coupled withN-phthalylamino acids such as 2b to give the products 3b using DCC orother conventional peptide coupling reagent. 3b may be deprotected andcyclized to 9 (R¹ =H, R³ =X¹¹ X⁹ H) by treating with hydrazine.Alternatively, 3b may be first alkylated by treatment with sodiumhydride followed by an alkyl halide in dimethylformamide (DMF) to givethe alkyl derivative 3. Treating this product with hydrazine gives theN¹ -alkylbenzodiazepine, 9 (R³ =X¹¹ X⁹ H).

9 (R³ =X¹¹ X⁹ H) are alkylated by treatment with alkyl halide or dialkylsulfate or acylated by treatment with acid halides or anhydrides,preferably in the presence of base such as triethyl amine. The productsare the alkyl and acyl derivatives 9 (R³ =X¹¹ X⁹ (CH₂)_(q) R⁷ and R³ =##STR21##

Alternatively, protection of the 3-amino function in 9 (R³ =X¹¹ NH₂),preferably with benzylchloroformate affords the acyl derivative 27.Treatment of this material with P₂ S₅ or preferably with Lawesson'sreagent in toluene gives the thioamide 28 which is converted to theamine 29 with Raney nickel in ethanol. Deprotection of the resultingproduct 29 via hydrogenolysis, or preferably by the action ofhydrobromic acid, yields the corresponding amino compound 30. Alkylationof 30 by treatment with alkyl halide or dialkyl sulfonate or acylationwith carboxylic acid halide or carboxylic acid anhydride in the presenceof an acid binding agent such as triethylamine or preferably with acarboxylic acid in the presence of a peptide coupling reagent such asdicyclohexyl-carbodiimide gives the alkyl or acyl derivatives 3 l.

3,5-Disubstituted benzodiazepines 7 (Scheme I) are also treated withsodium hydride in dimethylformamide (DMF), followed by an alkyl halide,to give the 1-alkyl derivatives 9. These or the parent 1-unsubstitutedcompound 7 are reduced, preferably with sodium cyanoborohydride andacetic acid at 15°, to give the corresponding 4,5-dihydro compounds 10.These are alkylated on N₄ by treatment with alkyl halide or dialkylsulfate. Alternatively, the 4,5-dihydro compounds are acylated on N₄ bytreatment with acyl halides or anhydrides, Preferably in the presence ofbase such as triethylamine. The products are the alkyl and acylderivatives 11. Alternatively, where R¹ is --X¹² COOR⁶ (R⁶ notH), 9 aretreated with a base such as sodium hydroxide in methanol to give theacids 9 (R¹ =X¹² COOH).

The 3,5-disubstituted benzodiazepines 7 are treated with alkyl- orarylmagnesium halides, preferably methylmagnesium iodide, to give thedihydro compounds 12. The products are alkylated and acylated onnitrogen, as described for the 3,5-disubstituted-4,5-dihydroderivatives, to give the derivatives 13.

The 3,5-disubstituted benzodiazepines 7 are treated with P₂ S₅ orLawesson's reagent(2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadi-phosphetane) togive the 2-thiones 14. These are reduced with Raney nickel to the2-unsubstituted compounds 15. The latter may be alkylated with alkylhalide or sulfate, acylated with acyl halide or anhydride, reduced withsodium cyanoborohydride, or substituted with alkyl- or aryl magnesiumhalide as described for 7 above.

Where the 3-position in a 3,5-disubstituted benzodiazepine 7 bears asubstituent containing an indole moiety, preferably 3-indolylmethyl,reduction with triethylsilane/TFA provides the corresponding indoline16. Alternatively, oxidation with HCl-dimethylsulfoxide provides theoxindole 17. 16 and 17 may be subjected to the reactions described for 7to obtain alkyl, acyl, and dihydro derivatives. Dialkyl, alkylacyl, andtrialkyl compounds may also be made using these methods.

The 3,5-disubstituted benzodiazepines 7 may also be oxidized, preferablywith m-chloroperoxybenzoic acid, to give the corresponding 4-N-oxides7a.

Alternatively, (Scheme II) 3-unsubstituted-5-substituted-1-substitutedor unsubstituted benzodiazepines 9 (R¹ =H) (Scheme II) prepared asdescribed in the prior art may be treated with base, preferably lithiumdiisopropylamide, in an inert solvent, preferably THF, according to theprocedure of J. Org. Chem., 46 4945 (1981). The resulting salt may bealkylated to obtain 9 with, for example, benzyl bromide or graminemethiodide. The resulting racemates may be resolved to obtain thepreferred 3(R) enantiomers, or may be used as such.

Alternatively, the salt may be treated with an alkyl or aryl aldehyde,ketone, or acid halide or anhydride to give the 1-hydroxymethylenecompounds ##STR22## or the 1-ketomethylene derivatives ##STR23## If theacid halide reaction is carried out in solvent containing peroxide, the3- and 5-hydroxy analogs 20 and 21 (resp.) may be obtained.

The hydroxymethylene compounds ##STR24## may be treated with acids,preferably trifluoroacetic acid, to obtain the olefins 18, 19, and/or22.

Alternatively, 3-substituted benzodiazepines 9 may be obtained bytreating the 3-unsubstituted compound 9 (R³ =H) with1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and alkylating agent such asalkyl halide or sulfate or, preferably, gramine methiodide. Resolutionto obtain the preferred 3(R) enantiomer may be carried out as describedabove.

3-Amino-5-substituted-1-substituted or unsubstituted benzodiazepines 9(R³ --NH₂) are prepared as described in the prior art. Alternatively, 9(R³ =NH₂) are prepared as shown in Scheme IVa. Treatment of the3-unsubstituted comPound 9 (R³ =H) with a suitable base, preferablypotassium t-butoxide, followed by a nitrosating agent, preferablyisoamyl nitrate, provides the oxime 9 (R³ ==NOH). Reduction, preferablywith Raney nickel, gives the 3-amino compounds 9 (R³ =NH₂).Alternatively, 9 (R³ =NH₂) are prepared by the method disclosed in U.S.Pat. No. 4,628,084.

3-Amino and 3-aminomethyl-5-substituted-1-substituted or unsubstitutedbenzodiazepines 23 (Scheme III) are alkylated with alkyl halides or withα-halo acids and esters to give the alkyl derivatives 24 (R³ =X¹¹NH(CH₂)_(q) R⁷) and 9 ##STR25## With acyl halides, the amines 23 givethe corresponding amides 24 ##STR26##

With isocyanates, the amines 23 give the corresponding ureas ##STR27##With N-protected or unprotected α-amino acids and a coupling reagentsuch as DCC, EDC, or isobutyl chloroformate, the amines 23 give theamides ##STR28##

3-Hydroxy-5-substituted-7-substituted or unsubstituted-1-substituted orunsubstituted benzodiazepines 24 (R³ =OH) (Scheme IIIb) are acylatedwith acyl halides to give the esters ##STR29##

3-Chloro-5-substituted-1-substituted or unsubstituted benzodiazepines 24(R³ =Cl) (Scheme IV) may be used to monoalkylate amines to give the3-substituted amino compounds 24 (R³ =NH₂). The 3-chloro compounds 29may also be used to monoalkylate 1,2-ethanediamine and1,3-propanediamine to give the compounds 24 (R³ =NH(CH₂)NH₂). These maybe alkylated to provide 24 (R³ =NHX¹¹ NH(CH₂)qR⁷) or acylated to give##STR30## Alternatively, the latter two compounds may be obtained fromthe previously mono-alkylated or acylated diamine and chloro compound 24(R³ =Cl).

3-Substituted-5-substituted-7-substituted or unsubstitutedbenzodiazepines 24 (R¹ =H) (Scheme IIIc) may be treated with sodiumhydride in a suitable solvent, such as DMF, followed by an alkyl halideto provide the 1-alkyl derivatives 24. When an acrylate such as methylor ethyl acrylate or acylonitrile is substituted for the alkyl halide,the 1-(2-substituted)ethyl compounds ##STR31## are obtained.

When R³ contains R⁷ where R⁷ is 1-unsubstituted-2- or 3-indolyl (SchemeIIId), the compounds 24 may be further alkylated by treatment withsodium hydride followed by an alkyl halide or an acrylate, such asmethyl or ethyl acrylate or acrylonitrile, or an activated amino acidsuch as Boc-phenylalanine anhydride to give the corresponding1-substituted indole compounds 24 (Scheme IIId) in which R⁸ is asdefined herein and R⁸ is other than hydrogen.

The compounds 24 wherein R¹ and/or R⁸ is X¹² --COOMe or X¹² --COOEt maybe treated with sodium hydroxide in an aqueous solvent, preferablyaqueous solvent, preferably aqueous methanol, and then acidified to givethe corresponding acids 24, wherein R¹ and/or R⁸ is X¹² COOHAlternatively, these same compounds may be treated with aqueous oranhydrous ammonia to give the amides 24 wherein R¹ and/or R⁸ is X¹²CONH₂.

In cases where the starting materials are optically active, thechirality at C₃ is controlled by the synthesis. When racemic startingmaterials are employed, racemic products are obtained. The enantiomersmay be separated by resolution.

In Vitro Activity of Compounds of Formula I

The biological activity of the compounds of Formula I have beenevaluated using 1.)an ¹²⁵ I-CCK receptor binding assay and in vitroisolated tissue preparations and 2.) ¹²⁵ I-gastrin and ³ H-pentagastrinbinding assays.

Materials and Methods 1. CCK Receptor Binding (Pancreas)

CCK-33 was radiolabeled with ¹²⁵ I-Bolton Hunter reagent (2000 Ci/mmole)as described by Sankara et al. (J. Biol. Chem. 254: 9349-9351, 1979).Receptor binding was performed according to Innis and Snyder (Proc.Natl. Acad. Sci. 77: 6917-6921, 1980) with the minor modification ofadding the additional protease inhibitors, phenylmethane sulfonylfluoride and o-phenanthroline. The latter two compounds have no effecton the ¹²⁵ I-CCK receptor binding assay.

Male Sprague-Dawley rats (200-350 g) were sacrificed by decapitation.The whole pancreas was dissected free of fat tissue and was homogenizedin 20 volumes of ice-cold 50 mM, Tris HCl (pH 7.7 at 25° C.) with aBrinkmann Polytron PT 10. The homogenates were centrifuged at 48,000 gfor 10 min. Pellets were resuspended in Tris Buffer, centrifuged asabove and resuspended in 200 volumes of binding assay buffer (50 mM TrisHCl, pH 7.7 at 25° C., 5 mM dithiothrietol, 0.1 mM bacitracin, 1.2 mMphenylmethane sulfonyl fluoride and 0.5 mM o-phenanthroline). For thebinding assay, 25 μl of buffer (for total binding) or unlabeled CCK-8sulfate to give a final concentration of 1 μM (for nonspecific binding)or the compounds of Formula I (for determination of inhibition of ¹²⁵I-CCK binding) and 25 μl of ¹²⁵ I-CCK-33 (30,000-40,000 cpm) were addedto 450 μl of the membrane suspensions in microfuge tubes. All assayswere run in duplicate or triplicate. The reaction mixtures wereincubated at 37° C. for 30 minutes and centrifuged in a BeckmanMicrofuge (4 minutes) immediately after adding 1 ml of ice-coldincubation buffer. The supernatant was aspirated and discarded, pelletswere counted with a Beckman gamma 5000. For Scatchard analysis (Ann.N.Y. Acad. Sci. 51: 660, 1949), ¹²⁵ I-CCK-33 was progressively dilutedwith increasing concentrations of CCK-33.

2. CCK Recepto Binding (Brain)

CCK-33 was radiolabeled and the binding was Performed according to thedescription for the Pancreas method with modifications according toSaito et al., J. Neurochem. 37:483-490, 1981.

Male Hartley guinea pigs (300-500 g) were sacrificed by decapitation andthe brains were removed and placed in ice-cold 50 mM, Tris HCl plus 7.58g/l Trizma-7.4 (pH 7.4 at 25° C.). Cerebral cortex was dissected andused as a receptor source. Each gram of fresh guinea pig brain tissuewas homogenized in 10 ml of Tris/Trizma buffer with a Brinkman polytronPT-10. The homogenates were centrifuged at 42,000 g for 15 minutes.Pellets were resuspended in Tris Buffer, centrifuged as above andresuspended in 200 volumes of binding assay buffer (10 mMN-2-hydroxyethyl-piperazine-N'-2-ethane sulfonic acid (HEPES), 5 mMMgCl₂, 0.25 mg/ml bacitracin, 1 mM ethyleneglycol-bis-(β-aminoethylether-N,N'-tetraacetic acid) (EGTA), and 0.4%bovine serum albumin (BSA)). For the binding assay, 25 μl of buffer (fortotal binding) or unlabeled CCK-8 sulfate to give a final concentrationof 1 μm (for nonspecific binding) or the compounds of Formula I (fordetermination of inhibition of ¹²⁵ I-CCK binding) and 25 μl of ¹²⁵I-CCK-33 (30,000-40,000 cpm) were added to 450 μl of the membranesuspensions in microfuge tubes. All assays were run in duplicate ortriplicate. The reaction mixtures were incubated at 25° C. for 2 hoursand centrifuged in a Beckman Microfuge (4 minutes) immediately afteradding 1 ml of ice-cold incubation buffer. The supernatant was aspiratedand discarded, pellets were counted with a Beckman gamma 5000.

The compounds of Formula I can be determined to be competitiveantagonists of CCK according to the following assays.

3. Isolated guinea pig gall bladder

Male Hartley guinea pigs (400-600 g) are sacrificed by decapitation. Thewhole gall bladder is dissected free from adjacent tissues and cut intotwo equal halves. The gall bladder strips are suspended along the axisof the bile duct in a 5 ml organ bath under 1 g tension. The organ bathcontains a Kreb's bicarbonate solution (NaCl 118 mM, KCl 4.75 mM, CaCl2.54 mM, KH₂ PO₄ 1.19 mM, Mg SO₄ 1.2 mM, NaHCO₃ 25 mM and dextrose 11mM) maintained at 32° C. and bubbled with 95% O₂ and 5% CO₂. Isometriccontractions are recorded using Statham (60 g; 0.12 mm) strain gaugesand a Hewlett-Packard (77588) recorder. The tissues are washed every 10minutes for 1 hour to obtain equilibrium prior to the beginning of thestudy. CCK-8 is added cumulatively to the baths and EC₅₀ 's determinedusing regression analysis. After washout (every 10 minutes for 1 hour),the compound of Formula I is added at least 5 minutes before theaddition of CCk-8 and the EC₅₀ of CCK-8 in the Presence of the compoundof Formula I similarly determined.

4. Isolated longitudinal muscle of guinea pig ileum

Longitudinal muscle strips with attached nerve plexus are prepared asdescribed in Brit. J. Pharmac. 23: 356-363, 1964; J. Physiol. 194:13-33, 1969. Male Hartley guinea pigs are decapitated and the ileumremoved (10 cm of the terminal ileum is discarded and the adjacent 20 cmpiece used). A piece (10 cm) of the ileum is stretched on a glasspipette. Using a cotton applicator to stroke tangentially away from themesentery attachment at one end, the longitudinal muscle is separatedfrom the underlying circular muscle. The longitudinal muscle is thentied to a thread and by gently pulling, stripped away from the entiremuscle. A piece of approximately 2 cm is suspended in 5 ml organ bathcontaining Krebs solution and bubbled with 95% O₂ and 5% CO₂ at 37° C.under 0.5 g tension. CCK-8 is added cumulatively to the baths and EC₅₀values in the presence and absence of compounds of Formula I determinedas described in the gall bladder protocol (above).

Gastrin Antagonism

Gastrin antagonist activity of compounds of Formula I is determinedusing the following assay.

Gastrin Receptor Binding in Guinea Pig Gastric Glands Preparation ofguinea pig gastric mucosal glands

Guinea pig gastric mucosal glands were prepared by the procedure ofBerglingh and Obrink Acta Physiol. Scand. 96: 150 (1976) with a slightmodification according to Praissman et al. C. J. Receptor Res. 3:(1983). Gastric mucosa from guinea pigs (300-500 g body weight, maleHartley) were washed thoroughly and minced with fine scissors instandard buffer consisting of the following: 130 mM NaCl, 12 mM NaHCO₃,3 mM NaH₂ PO₄, 3 mM Na₂ HPO₄, 3 mM K₂ HPO₄, 2 mM MgSO₄, 1 mM CaCl₂, 5 mMglucose and 4 mM L-glutamine, 25 mM HEPES at pH 7.4. The minced tissueswere washed and then incubated in a 37° C. shaker bath for 40 minuteswith the buffer containing 0.1% collagenase and 0.1% BSA and bubbledwith 95% O₂ and 5% CO₂. The tissues were passed twice through a 5 mlglass syringe to liberate the gastric glands, and then filtered through200 mesh nylon. The filtered glands were centrifuged at 270 g for 5minutes and washed twice by resuspension and centrifugation.

Binding studies

The washed guinea pig gastric glands prepared as above were resuspendedin 25 ml of standard buffer containing 0.25 mg/ml of bacitracin. Forbinding studies, to 220 μl of gastric glands in triplicate tubes, 10 μlof buffer (for total binding) or gastrin (1 μM final concentration, fornonspecific binding) or test compound and 10 μl of ¹²⁵ I-gastrin (NEN,2200 Ci/mmole, 25 pM final) or ³ H-pentagastrin (NEN 22 Ci/mmole, 1 nMfinal) were added. The tubes were aerated with 95% O₂ and 5% CO₂ andcapped. The reaction mixtures after incubation at 25° C. for 30 minuteswere filtered under reduced pressure on glass G/F B filters (Whatman)and immediately washed further with 4×4 ml of standard buffer containing0.1% BSA. The radioactivity on the filters was measured using a Beckmangamma 5500 for ¹²⁵ I-gastrin or liquid scintillation counting for ³H-pentagastrin.

In Vitro Results 1. Effect of The Compounds of Formula I on ¹²⁵ I-CCK-33receptor binding

The preferred compounds of Formula I are those which inhibited specific¹²⁵ I-CCK-33 binding in a concentration dependent manner.

Scatchard analysis of specific ¹²⁵ I-CCK-33 receptor binding in theabsence and presence of the compounds of Formula I indicated thecompound of Formula I competitively inhibited specific ¹²⁵ I-CCK-33receptor binding since it increased the K_(D) (dissociation constant)without affecting the B_(max) (maximum receptor number). A K_(i) value(dissociation constant of inhibitor) of the compounds of Formula I wasestimated.

The data of Table 1 were obtained for compounds of Formula I.

                  TABLE I                                                         ______________________________________                                        CCK Receptor Binding Results                                                         IC.sub.50 (uM)                                                         Compound of                                                                            .sup.125 I-CCK                                                                            .sup.125 I-CCK                                                                          .sup.125 I-Gastrin                             Example  Pancreas    Brain     Gastric Glands                                 ______________________________________                                         1       67          >100      167                                            2 & 3    0.4         81.5      40                                             4a & 44  0.36        16.       49                                               4b     0.27        18        8                                               5       3.4         100       30                                              6       1.2         50        100                                             7       >100        100       >100                                            8       100         100       227                                             9       10.7        48        78                                              10      16.7        >100      47                                              12      4           >100      28                                              13      80          100       >100                                            14      42          60        12                                              15      60          80        38                                              16      >100        >100      128                                             17      23          100       200                                             18      49          61        62                                              19      33          >100      14                                              20      >100        >100      >100                                            21      100         >100      200                                             22      21          >100      161                                             23      10          >100      200                                             24      11          >100      161                                             25      12          >100      139                                             26      75          >100      100                                             27a     >100        >100      >1000                                           27b     100         >100      > 1000                                          28      5           >100      200                                             29      48          >100      80                                              30      >100        >100      >1000                                           31      1.4         >100      200                                             32      10.6        36        >100                                            33      >100        >100      238                                             34      4.5         >100      167                                             35      10          15        >100                                            36      0.3         30        >100                                            37      2.2         30        58                                              38      100         >100      >100                                            39      100         30        23                                              40      3.6         >100      >100                                            41      100         >100      25                                              42      8.3         >100      24                                              43      0.3         23        5                                               45      10.6        >100      >1000                                           46      >100        >100      >1000                                           47      24          40        24                                              48      54          33        8.4                                             49      >100        100       34                                              50a     15          2.6       1.2                                             50b     100         40        61                                              51      >100        32        25                                              52      >100        33        26                                              53a     100         4.2       0.85                                            53b     19          100       >100                                            55      7.6         38.6      76                                              57      2.9         100       700                                             58      18          12        24                                              59      1.4         >100      >100                                            60      1.3         100       120                                             62      >100        >100      >1000                                           63      >100        >100      >1000                                           65      >100        >100      >1000                                           66      22          100       7.4                                             67      22          100       47                                              68      7           30        >100                                            69      14          >100      350                                             70      15          100       200                                             73      0.0047      8         4                                               74      3           100       >100                                            75      4.8         100       4.7                                             76      1           11        32                                              77      6           20        250                                             78      0.0014      5.5       0.65                                            79a     0.0008      0.77      0.72                                            79b     0.0014      15        >2                                              80      0.0023      3.4       2.9                                             81a     0.0014      0.3       0.19                                            81b     0.0013      1         1.6                                             82      2.7         12        >100                                            83      0.7         13        26                                              84a     1.9         >40       >40                                             84b     100         >100      55                                              85a     100         >100      >100                                            85b     >100        >100      >100                                            87      0.0008      0.27      0.17                                            88      0.0006      0.3       0.027                                           89      0.019       1.1       0.24                                            90      0.049       11        5.2                                             91      0.0025      2.9       0.8                                             92      0.0043      1.6       0.62                                            93      0.7         2.9       2                                               94      0.053       3.8       3.8                                              95 Z   100         34        >100                                             95 E   25          33        >100                                            96      17          >100      500                                              97     20          >100      200                                             98      28          100       86                                              99      10          74        80                                             100      4           34        22                                             102      0.7         30        12.8                                           103      1.4         11        5.8                                            104      0.3         >100      >100                                           105      0.0021      3         4.6                                            106      0.11        >50       >10                                            107      0.049       50        >10                                            108      0.15        >50       >10                                            109      1.1         8.4       18                                             110      1           3.3       3.9                                            111      0.007       40        8.4                                            112      24          >50       >10                                            113      0.0015      5.6       0.39                                           114      0.005       12        4.8                                            115      0.022       3.5       >10                                            116      0.3         80        >10                                            118      0.071       38        >10                                            119      13          33        >10                                            120      0.12        50        >10                                            121      0.011       5.5       3.8                                            122      0.071       16        29                                             123      2.1         66        >10                                            124      0.25        100       >10                                            125      0.9         100       >10                                            126      0.2         29        >10                                            127      0.0047      7         6.3                                            128      0.009       32        11                                             129      0.11        1.9       0.69                                           130      0.041       >40       8.2                                            131      0.0083      40        6.7                                            132      0.032       >100      8.2                                            133      0.9         >40       110                                            134      0.015       40        9.5                                            135      0.021       >40       5                                              136      0.096       >40       5.4                                            137      7.5         >40       52                                             138      58          100       >100                                           139      3.4         >100      30                                             140      0.081       75        4.3                                            141      0.029       > 40      25                                             142      0.066       18        2.4                                            143      0.22        23        8                                              144      0.48        43        9.4                                            145      0.24        65        36                                             146      1.4         100       40                                             147      0.5         >100      180                                            148      1.8         100       31                                             149      0.73        >100      22                                             150      1.7         83        130                                            151      11          22        7.5                                            152      0.27        >100      >100                                           153      1.7         >40       >40                                            154      0.0035      3.5       0.5                                            155      1.5         >100      128                                            156      0.0035      4         0.68                                           157      0.019       8         2.4                                            158      0.11        100       25                                             159      0.0034      3         0.53                                           160      0.020       12        14                                             161      6.2         70        19                                             162      0.043       31        9                                              163      3.6         12        80                                             164      100         18        >100                                           165      27          8         >100                                           166      1.6         12        29                                             167      0.00075     1.7       0.39                                           168      0.015       2.4       2                                              169      58          3.8       4.4                                            170      0.8         45        11                                             171      9           5.6       5.8                                            172      3.4         16        3.7                                            173      0.15        >40       28                                             174      5.5         >40       18                                             175      0.7         15        8                                              176      1.0         10        3.2                                            177      0.018       3.7       0.55                                           178      4.9         >100      >100                                           179      4.4         3.6       18                                             180      0.016       >100      11                                             181      0.002       9.3       4.4                                            182      0.11        0.3       0.26                                           185      0.73        >100      22                                             186      3.1         >100      >100                                           187      0.003       1.3       5.3                                            188      >30         3.2       1.3                                            189      1.1         >100      73                                             190      0.78        >100      130                                            191      0.80        >100      >100                                           192      0.0003      0.64      0.18                                           193      1.6         >100      13                                             194      0.22        0.0012    0.004                                          195      4.8         >0.1      0.4                                            196      0.0009      2.4       1.9                                            197      1.9         5.9       10                                             198      >10         18        1.5                                            199      3.2         54        100                                            200      0.1         63        67                                             201      0.25        >100      >100                                           202      0.056       0.072     0.12                                           203      0.0013      4.6       6.2                                            204      0.37        0.001     0.0033                                         205      35          >0.3      33                                             206      12          >100      >100                                           207      115         3.3       4.2                                            208      1.3         0.044     0.14                                           209      2.2         0.3       0.3                                            210      0.3         10        21                                             211      13          93        6.7                                            212      1.9         0.4       0.6                                            213      2.1         0.38      0.28                                           214      0.003       0.22      0.12                                           215      4.8         1.8       0.56                                           216      0.001       2.4       1.7                                            217      0.051       0.023     0.022                                          218      0.0026      1.8       1.8                                            219      0.0005      1.4       0.44                                           220      2.4         0.10      0.15                                           221      0.4         0.0006    0.002                                          222      2.2         0.15      0.23                                           223      0.14        >100      >100                                           224      2.1         0.011     0.025                                          225      4.7         >100      130                                            226      <0.1        2.3       6.4                                            227      6.6         50        >100                                           228      0.049       100       60                                             229      1.2         0.44      0.26                                           230      0.49        0.0051    0.035                                          231      0.58        2.7       2.9                                            232      0.34        1.0       1.2                                            233      0.026       0.41      0.58                                           234      1.1         0.0055    0.012                                          235      29          1.7       1.4                                            236      0.52        0.00028   0.0005                                         237      1.2         0.008     0.0026                                         238      0.028       26        11                                             239      1.7         0.038     0.0045                                         240      1.3         2.9       7                                              241      0.93        1.4       0.95                                           242      0.9         2.3       0.87                                           243      0.68        2.8       3.6                                            244      0.95        0.74      0.5                                            245      7.2         92        12                                             246      0.0019      0.002     0.0024                                         247      0.0062      0.003     0.0016                                         248      20          5.3       2.2                                            249      0.41        0.022     0.012                                          250      0.0083      0.032     0.009                                          251      0.49        0.86      0.42                                           252      0.057       0.006     0.0035                                         253      0.16        0.02      0.045                                          254      0.0009      0.32      0.11                                           255      0.13        0.048     0.032                                          256      0.21        0.046     0.0098                                         257      0.026       0.067     0.048                                          258      0.003       0.22      0.06                                           259      0.046       0.066     0.014                                          260      6.8         38        >1                                             261      0.43        11        3.2                                            262      2.4         3         0.39                                           263      0.0081      0.0071    0.0031                                         264      0.034       0.011     0.006                                          265      0.0082      0.0098    0.0031                                         266      0.60        0.0022    0.0013                                         267      0.0013      0.29      0.19                                           268      0.33        2.1       0.42                                           269      45          0.69      0.45                                           270      0.003       1.2       0.5                                            271      0.01        0.054     0.01                                           272      0.0044      0.005     0.0028                                         273      0.0086      0.079     0.057                                          274      0.31        2.3       1.6                                            275      0.020       0.11      0.12                                           276      0.00039     0.28      0.24                                           277      0.018       0.86      2.6                                            278      0.6         1.2       1                                              279      0.011       0.31      0.6                                            280      0.015       0.97      0.25                                           281      1.4         0.003     0.00066                                        282      0.84        0.0038    0.0016                                         283      1.1         71        66                                             284      0.017       0.00034   0.0005                                         285      >0.1        0.00022   0.00026                                        286      >0.1        0.0038    0.0015                                         287      0.00074     1.0       0.95                                           288      0.075       0.042     0.054                                          289      0.0001      0.089     0.66                                           290      0.002       0.015     0.0087                                         291      0.00008     0.38      0.71                                           292      0.001       0.0035    0.0115                                         293      3.1         0.0065    0.0025                                         294      0.0001      0.038     0.04                                           295      0.003       0.015     0.034                                          296      0.29        0.0075    0.0022                                         297      1.8         3.7       5.2                                            ______________________________________                                    

Preferred compounds of Formula I are those compounds wherein:

R¹ is H, C₁ -C₆ linear or branched alkyl, --X¹² COOR⁶, --X¹¹-cycloloweralkyl, X¹² NR⁴ R⁵ or --X¹² CONR⁴ R⁵ ;

R² is substituted or unsubstituted phenyl (wherein the substitutents maybe 1 or 2 of halo, loweralkyl, loweralkoxy, loweralkylthio, carboxyl,carboxyloweralkyl, nitro, --CF₃, or hydroxy), 2-, 3-, or 4-pyridyl,##STR32## R⁴ and R⁵ are independently R⁶ or in combination wiht the N ofthe NR⁴ R⁵ group form an unsubstituted or mono or disubstituted,saturated or unsaturated, 4-7 membered heterocyclic ring, or benzofused4-7 membered heterocyclic ring or said heterocyclic ring or saidbenzofused heterocyclic ring which further comprises a second heteroatomselected from O and NCH₃ and the substituent(s) is/are independentlyselected from C₁₋₄ alkyl;

R⁶ is H, C₁ -C₄ straight or branched-chain alkyl or C₃ -C₆ -cycloalkyl

R⁷ is α- or β-naphthyl, substituted or unsubstituted phenyl (wherein thesubstituent may be 1 to 2 of halo, --NO₂, --OH, --X¹¹ NR⁴ R⁵,loweralkyl, CF₃, CN, SCF₃, ##STR33## SH, SPh, loweralkoxy,loweralkylthio, or carboxy), 2-, 3-, 4-pyridyl, ##STR34## R⁸ is H,loweralkyl or cycloloweralkyl; R⁹ and R¹⁰ are independently H, --OH, or--CH₃ ;

R¹³ is H, loweralkyl, acyl, O, or cycloloweralkyl;

R¹⁸ is H or loweralkyl;

p is 0 when its adjacent --- is unsaturated and 1 when its adjacent ---is saturated except that when is R¹³ is O, p=1 and --- is unsaturated;

q is 0-2;

r is 1 or 2;

X¹ is H, --NO₂, CF₃, CN, loweralkyl, halo, loweralkylthio or --X¹¹ COOR⁶;

X² and X³ are independently H, --NO₂, halo, loweralkylthio, loweralkyl,or loweralkoxy;

X⁴ is S, O, or NR⁸ ;

X⁵ is H, CF₃, CN, --COOR⁶, NO₂, or halo;

X⁶ is O or HH;

X⁷ is O, S;

X⁹ and X⁹ _(a) are independently NR¹⁸, or O;

X¹¹ is absent or C₁₋₄ linear alkylidene;

X¹² is C₁₋₄ linear or branched alkylidene;

--- is a saturated or unsaturated bond

and the pharmaceutically acceptable salts thereof.

More preferred compounds of Formula I are wherein:

R¹ is H, C₁ -C₃ linear or branched alkyl, --X¹² COOR⁶, --X¹² CONR⁴ R⁵,

R² is substituted or unsubstitted phenyl (wherein

the substitutents may be 1 or 2 of halo,

loweralkyl, carboxyl, nitro or --CF₃); --X¹² COOR⁶ ; 2--, 3--, 4--pyridyl; ##STR35## R⁴ and R⁵ are independently R⁶ or in combination withthe N of the NR⁴ R⁵ group form an unsubstituted or mono ordisubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring,or benzofused 4-7 membered heterocyclic ring or said heterocyclic ringor said benzofused heterocyclic ring which further comprises a secondheteroatom selected from O and NCH₃ and the substituent(s) is/areindependently selected from C₁₋₄ alkyl;

R⁶ is H, C₁ -C₄ straight or branched-chain alkyl;

R⁷ is α- or β-naphthyl, substituted or unsubstituted phenyl (wherein thesubstituents may be 1 to 2 of halo, --NO₂, --OH, --NR⁴ R⁵, loweralkyl,CF₃, CN, or loweralkoxy), 2-, 3-, 4-pyridyl, ##STR36## R⁹ and R¹⁰ areindependently H, or --OH; p is 0 when its adjacent --- is unsaturatedand 1 when its adjacent --- is saturated, the p of (R¹³)_(p) is 0;

r is 1 or 2;

X¹ is H, --NO₂, CF₃, loweralkyl or halo;

X² and X³ are independently H, --NO₂, halo, loweralkyl, or loweralkoxy;

X⁴ is O or NR⁸ ;

X⁷ is O or S,

X¹² is C₁₋₂ linear or branched alkylidene;

--- is a saturated or unsaturated bond;

and the pharmaceutically acceptable salts thereof.

Even more preferred compounds of Formula I are wherein:

R¹ is H, C₁ -C₂ linear alkyl, --X¹² COOR⁶, --X¹² CONR⁴ R⁵ ;

R² is substituted or unsubstituted phenyl (wherein the substitutent maybe halo, loweralkyl, nitro, --CF₃), 2-, 3-, 4-pyridyl, or X¹² COOR⁶ ;

R³ is ##STR37## R⁴ and R⁵ are independently R⁶ or in combination withthe N of the NR⁴ R⁵ group form an unsubstituted or mono ordisubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring,or benzofused 4-7 membered heterocyclic ring or said heterocyclic ringor said benzofused heterocyclic ring which further comprises a secondheteroatom selected from O and NCH₃ and the substituent(s) is/areindependently selected from C₁₋₄ alkyl;

R⁶ is H, C₁ -C₃ straight chain alkyl;

R⁷ is α- or β-naphthyl, substituted or unsubstituted phenyl (wherein thesubstituents may be 1 to 2 of halo, --NO₂, NH₂, methyl, ethyl, CF₃, CN,or loweralkoxy), 2-, 3-, 4- pyridyl, ##STR38## R¹⁰ is H, or OH; p is 1of (R¹⁰)_(p) and O of (R⁹)_(p) and (R¹³)_(p), --- at 4,5 is unsaturatedand --- at 3,4 is saturated;

r is 1 or 2;

X¹ is H, --NO₂, CF₃, loweralkyl or halo;

X₂ is H, --NO₂, halo or loweralkyl;

X⁴ is O, NH, NCH₃ ;

X⁷ is O or S;

X¹² is C₁₋₂ linear alkylidene;

and the pharmaceutically acceptable salts thereof.

Yet even more preferred compounds of Formula I are wherein:

R¹ is H, CH₃, CH₂ CH₃, CH₂ COOH, CH₂ COOEt, CH₂ CON(Et)₂, ##STR39## R²is phenyl, 2-F-phenyl, 4-CH₃ -phenyl, 2-, 3-, or 4-pyridyl; R³ is##STR40## R¹⁰ is H or --OH; p is 1 of (R¹⁰)_(p) and o of (R_(p) ⁹) and(R¹³)_(p) ; --- at 4, 5 is aunsaturated and --- at 3, 4 is saturated;

r is 1;

X¹ is H, 7-Cl, 8-CH₃, 9-CH₃ ;

X⁷ is O or S;

and the pharmaceutically acceptable salts thereof.

The most preferred compounds of Formula I are:

3(R)-N-(4-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl)urea,

3-Benzoyl-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,

5-(2-Fluorophenyl)-1,3-dihydro-3-hydroxy-3-(4-methoxybenzoyl)-1-methyl-2H-1,4-benzodiazepin-2-one,

N-(2,3-Dihydro-1-methyl-2-oxo-5(3-methylphenyl)-1H-1,4-benzodiazepin-3-yl)-N'-(phenylmethyl)urea,

N-(2,3-Dihydro-1-ethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)urea,

3-(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(3-methoxyphenyl)-2-propenamide,

3-((((4-Chlorophenyl)amino)carbonyl)amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-propanoicacid ethyl ester,

3(RS)-1,3-dihydro(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,

1-Carboxymethyl-1,3-dihydro-3(RS)-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-3(RS)-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,

1,3-dihydro-1-methyl-3(RS)-[2-(1-methylindole)carbonylamino]-5-phenyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-1-methyl-3(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-5-(2-fluorophenyl)-1-methyl-3(RS)-[2'-(1'-methylindole)carbonylamino]-2H-1,4-benzodiazepin-2-one,

3(S)-(-)-1,3-Dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-1,3-Dihydro-3-(4-chlorobenzoylamino)-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,

3(S)-(-)-1,3-Dihydro-3-(4-bromobenzoylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,

1-Carboxymethyl-1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-3-(RS)-(5-fluoroindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-3-(RS)-(1-methylindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-benzofurancarbonylamino)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-1-methyl-3-(RS)-(4-chlorophenylcarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-3-(3-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-3-(4-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(4-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(3-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indole)carbonylamino-2H-1,4-benzodiazepin-2-thione,

3(S)-(2-Indolecarbonyl)amino-1,3-dihydro-5-phenyl-2H-1,4,-benzodiazepin-2-one,

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-bemzpdoazepin-3-yl)-3-phenyl-2-propenamide,

3-((((4-Chlorophenyl)amino)carbonyl)amino)-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

3-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-amino-4-chlorobenzamide

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,

3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

5-(2-Fluorophenyl)-2,3-dihydro-3-((1H-indol-2-ylcarbonyl)amino)-2-oxo-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

4-Bromo-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide,

N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,

(S)-N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)benzamide,

3-((((4-Chlorophenyl)amino)carbonyl)amino)-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide,

1-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)pyrrolidine,

1-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)-4-methylpiperazine,

3-(((4-Chlorophenyl)acetyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-N-(3-methoxyphenyl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxypeenyl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-phenylurea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea,

N-(2-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

N-(4-Nitrophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

N-(2,4-Dichlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-nitrophenyl)-urea,

N-(3-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-nitrophenyl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo--phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-fluorophenyl)-urea,

N-(3-Bromophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-1-naphthalenyl-urea,

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-chlorophenyl)-urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-bromophenyl)-urea,

1-{[3-[(((3-Methoxyphenyl)amino)carbonyl)amino]-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pyrrolidine,

3-{[((3-Methoxyphenyl)amino)carbonyl)amino]-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,

3-}[(((2-Chlorophenyl)amino)carbonyl]amino}-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide,

3-N(2,3-Dihydro-9-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,

3-N-(2,3-Dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

3-N-(2,3-Dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,

N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea,

3-N-(2,3-Dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-N-(2,3-Dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,

N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-ureaor

(R)-N-(2,3-Dihydro-1-methyl-2-oxo=5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-chlorophenyl)-urea.

In another aspect of the invention is that some of the compounds ofFormula I are specific for CCK as compared to gastrin and vice-versa.What is meant by a compound that is "specific" for CCK is that suchcompound is at least ten times more potent as an antagonist of CCK ascompared to gastrin and vice-versa for a compound that is specific forgastrin. Such specificity is hightly desirable because CCK specificcompound can be utilized with little interference with gastrinreceptors. Similarly, a gastrin specific compound can be utilized withessentially no interference with the CCK receptors.

Examples of CCK specific compounds of Formula I are:

3(RS)-1,3-Dihydro(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,

1-Carboxymethyl-1,3-dihydro-3(RS)-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2one,

1,3-Dihydro-3(RS)-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

1,3-dihydro-1-methyl-3(RS)-[2-(1-methylindole)carbonylamino]-5-phenyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-1-methyl-3(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-1-methyl-3(RS)-[2'-(1'-methylindole)carbonylamino]-2H-1,4-benzodiazepin-2-one,

3(S)-(-)-1,3-Dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,

3-(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-1,3-Dihydro-3-(4-chlorobenzoylamino)-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,

2(S)-(-)-1,3-Dihydro-3-(4-bromobenzoylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,

1-Carboxymethyl-1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-3-(RS)-(5-fluoroindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-3-(RS)-(1-methylindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-benzofurancarbonylamino)-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-1-methyl-3-(RS)-(4-chlorophenylcarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one,

3(S)-(+)-3-(3-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,

3-(S)-(+)-3-(4-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,

3-(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(4-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,

3-(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(3-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indole)carbonylamino-2H-1,4-benzodiazepin-2-thione,

3(S)-(2-Indolecarbonyl)amino-1,3-dihydro-5-phenyl-2H-1,4,-benzodiazepin-2-one,

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-propenamide,

3N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-amino-4-chlorobenzamide,

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,

5-(2-Fluorophenyl)-2,3-dihydro-3-((1H-indol-2-ylcarbonyl)amino)-2-oxo-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

4-Bromo-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide,

N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,

(S)-N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,

N-(2-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

N-(2,4-Dichlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-nitrophenyl)-urea,

(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-chlorophenyl)-urea,

3-N-(2,3-Dihydro-9-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,

3-N-(2,3-Dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,

3-N-(2,3-Dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,

N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-urea,

3-N-(2,3-Dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamideand

N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea.

Examples of gastrin specific compounds of Formula I are:

3-((((4-Chlorophenyl)amino)carbonyl)amino)-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

3-((((4-Chlorophenyl)amino)carbonyl)amino)-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide,

1-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)pyrrolidine,

1-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)-4-methylpiperazine,

3-(((4-Chlorophenyl)acetyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-aceticacid ethyl ester,

N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-phenylurea,

N-(4-Nitrophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)N'-(3-methoxyphenyl)-urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-bromophenyl)-urea,

1-{[3-[(((3-Methoxyphenyl)amino)carbonyl)amino]-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pyrrolidine,

3-{[((3-Methoxyphenyl)amino)carbonyl)amino]-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,

3-{[((2-Chlorophenyl)amino)carbonyl]amino}-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea,

(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-chlorophenyl)-urea.

Examples of Compounds of Formula I are listed in Table 2.

                  TABLE 2                                                         ______________________________________                                         ##STR41##                                                                    X.sup.4 = NH, NCH.sub.3, O, or S                                              X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR42##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub. COOH                                                                              --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub. 2 COOEt                                                                           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                         ##STR43##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-F Ph   --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                         ##STR44##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   o-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                         ##STR45##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub. 2 COOt-Bu                                                                      --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                         ##STR46##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub. 2 COOEt                                                                           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   Ph       --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    OH                                 H    1     CH.sub.2 COOEt                                                                            --   Ph       --    OH                                 H    1     CH.sub.3    --   o-FPh    --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    OH                                 H    1     CO.sub.2 COOEt                                                                            --   o-FPh    --    OH                                 H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    OH                                 H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    OH                                 ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                         ##STR47##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub. 2 COOH                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                         ##STR48##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF   1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-F Ph   --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-F Ph   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-Cl Ph  --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                         ##STR49##                                                                    X.sub.4 = NH, NCH.sub.3, O, or S                                              X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   Ph       --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    OH                                 H    1     CH.sub.2 COOEt                                                                            --   Ph       --    OH                                 H    1     CH.sub.3    --   o-FPh    --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    OH                                 H    1     CO.sub.2 COOEt                                                                            --   o-FPh    --    OH                                 H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    OH                                 H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    OH                                 ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                         ##STR50##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub. 3   --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   Ph       --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    OH                                 H    1     CH.sub.2 COOEt                                                                            --   Ph       --    OH                                 H    1     CH.sub.3    --   o-FPh    --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    OH                                 H    1     CO.sub.2 COOEt                                                                            --   o-FPh    --    OH                                 H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    OH                                 H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    OH                                 H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    OH                                 ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                         ##STR51##                                                                    X.sup.1                                                                            r     R.sup.1     (R.sup.9).sub.p                                                                    R.sup.2  (R.sup.13).sub.p                                                                    (R.sup.10).sub.p                   ______________________________________                                        H    1     H           --   Ph       --    H                                  Cl   1     H           --   Ph       --    H                                  F    1     H           --   Ph       --    H                                  CF.sub.3                                                                           1     H           --   Ph       --    H                                  OH   1     H           --   Ph       --    H                                  NO.sub.2                                                                           1     H           --   Ph       --    H                                  H    1     CH.sub.3    --   Ph       --    H                                  Cl   1     CH.sub.3    --   Ph       --    H                                  F    1     CH.sub.3    --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   Ph       --    H                                  OH   1     CH.sub.3    --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   Ph       --    H                                  H    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  F    1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   Ph       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   Ph       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   Ph       --    H                                  H    1     H           --   o-FPh    --    H                                  Cl   1     H           --   o-FPh    --    H                                  F    1     H           --   o-FPh    --    H                                  CF.sub.3                                                                           1     H           --   o-FPh    --    H                                  OH   1     H           --   o-FPh    --    H                                  NO.sub.2                                                                           1     H           --   o-FPh    --    H                                  H    1     CH.sub.3    --   o-FPh    --    H                                  Cl   1     CH.sub.3    --   o-FPh    --    H                                  F    1     CH.sub.3    --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   o-FPh    --    H                                  OH   1     CH.sub.3    --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   o-FPh    --    H                                  H    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  F    1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  OH   1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   o-FPh    --    H                                  OH   1     CH.sub. 2 CH.sub.3                                                                        --   o-FPh    --    H                                  H    1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   o-FPh    --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   o-FPh    --    H                                  H    1     H           --   p-ClPh   --    H                                  F    1     H           --   p-ClPh   --    H                                  CF.sub.3                                                                           1     H           --   p-ClPh   --    H                                  OH   1     H           --   p-ClPh   --    H                                  H    1     CH.sub.3    --   p-ClPh   --    H                                  F    1     CH.sub.3    --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   p-ClPh   --    H                                  OH   1     CH.sub.3    --   p-ClPh   --    H                                  H    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  F    1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  OH   1     CH.sub.2 COOH                                                                             --   p-ClPh   --    H                                  H    1     CH.sub. 2 CH.sub.3                                                                        --   p-ClPh   --    H                                  H    1     CH.sub.2 COOEt                                                                            --   p-ClPh   --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   p-ClPh   --    H                                  H    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOt-Bu                                                                       --    H                                  H    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  F    1     H           --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     H           --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     H           --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.3    --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  Cl   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  F    1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  CF.sub.3                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  NO.sub.2                                                                           1     CH.sub.2 COOH                                                                             --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.3                                                                         --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 COOEt                                                                            --   CH.sub.2 COOEt                                                                         --    H                                  H    1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  OH   1     CH.sub.2 CH.sub.2 COOH                                                                    --   CH.sub.2 COOEt                                                                         --    H                                  ______________________________________                                    

                                      TABLE 13                                    __________________________________________________________________________    Compounds of the Formula                                                       ##STR52##                                                                    No.                                                                              R.sup.a                                                                         R.sup.1     R.sup.3                                                      __________________________________________________________________________    577                                                                              F CH.sub.2CF.sub.3                                                                           ##STR53##                                                   586                                                                              F H                                                                                          ##STR54##                                                   625                                                                              H H                                                                                          ##STR55##                                                   643                                                                              F (CH.sub.2).sub.2CN                                                                         ##STR56##                                                   648                                                                              F H                                                                                          ##STR57##                                                   651                                                                              F H                                                                                          ##STR58##                                                   652                                                                              H H                                                                                          ##STR59##                                                   659                                                                              F H                                                                                          ##STR60##                                                   665                                                                              H H                                                                                          ##STR61##                                                   666                                                                              F H                                                                                          ##STR62##                                                   668                                                                              F H                                                                                          ##STR63##                                                   676                                                                              F H                                                                                          ##STR64##                                                   677                                                                              F H                                                                                          ##STR65##                                                   678                                                                              F H                                                                                          ##STR66##                                                   679                                                                              H H                                                                                          ##STR67##                                                   686                                                                              F H                                                                                          ##STR68##                                                   688                                                                              F H                                                                                          ##STR69##                                                   690                                                                              F CH.sub.2CONH.sub.2                                                                         ##STR70##                                                   691                                                                              F H                                                                                          ##STR71##                                                   692                                                                              F H                                                                                          ##STR72##                                                   694                                                                              F H                                                                                          ##STR73##                                                   695                                                                              F H                                                                                          ##STR74##                                                   716                                                                              H H                                                                                          ##STR75##                                                   720                                                                              F H                                                                                          ##STR76##                                                   722                                                                              H H                                                                                          ##STR77##                                                   724                                                                              H H                                                                                          ##STR78##                                                   725                                                                              H CH.sub.3                                                                                   ##STR79##                                                   726                                                                              H CH.sub.3                                                                                   ##STR80##                                                   736                                                                              F H                                                                                          ##STR81##                                                   737                                                                              F H                                                                                          ##STR82##                                                   727                                                                              H CH.sub.3                                                                                   ##STR83##                                                   728                                                                              H CH.sub.3                                                                                   ##STR84##                                                   740                                                                              H H                                                                                          ##STR85##                                                   745                                                                              F H                                                                                          ##STR86##                                                   752                                                                              F H                                                                                          ##STR87##                                                   753                                                                              F H                                                                                          ##STR88##                                                   755                                                                              H H                                                                                          ##STR89##                                                   761                                                                              F CH.sub.3                                                                                   ##STR90##                                                   763                                                                              F H                                                                                          ##STR91##                                                   772                                                                              H H                                                                                          ##STR92##                                                   779                                                                              F                                                                                ##STR93##                                                                                 ##STR94##                                                   781                                                                              H H                                                                                          ##STR95##                                                   782                                                                              H H                                                                                          ##STR96##                                                   786                                                                              F                                                                                ##STR97##                                                                                 ##STR98##                                                   787                                                                              F H                                                                                          ##STR99##                                                   790                                                                              F CH.sub.3                                                                                   ##STR100##                                                  791                                                                              F H                                                                                          ##STR101##                                                  793                                                                              H H                                                                                          ##STR102##                                                  794                                                                              F CH.sub.3                                                                                   ##STR103##                                                  795                                                                              F CH.sub.3                                                                                   ##STR104##                                                  796                                                                              H H                                                                                          ##STR105##                                                  799                                                                              H H                                                                                          ##STR106##                                                  800                                                                              H H                                                                                          ##STR107##                                                  801                                                                              H H                                                                                          ##STR108##                                                  802                                                                              H H                                                                                          ##STR109##                                                  803                                                                              H H                                                                                          ##STR110##                                                  804                                                                              H H                                                                                          ##STR111##                                                  805                                                                              H H                                                                                          ##STR112##                                                  816                                                                              H H                                                                                          ##STR113##                                                  825                                                                              F CH.sub.3                                                                                   ##STR114##                                                  827                                                                              F CH.sub.3                                                                                   ##STR115##                                                  829                                                                              F CH.sub.3                                                                                   ##STR116##                                                  830                                                                              F CH.sub.3                                                                                   ##STR117##                                                  __________________________________________________________________________

Other compounds of Formula I are listed on the following table.

                                      TABLE 14                                    __________________________________________________________________________    No. Compound                                                                  __________________________________________________________________________    632                                                                                ##STR118##                                                               633                                                                                ##STR119##                                                               636                                                                                ##STR120##                                                               638                                                                                ##STR121##                                                               646                                                                                ##STR122##                                                               732                                                                                ##STR123##                                                               733                                                                                ##STR124##                                                               777                                                                                ##STR125##                                                               808                                                                                ##STR126##                                                               809                                                                                ##STR127##                                                               826                                                                                ##STR128##                                                               828                                                                                ##STR129##                                                               __________________________________________________________________________

The invention is further defined reference to the following preparationsand examples, which are intended to be illustrative and not limiting.

All temperatures are in degrees Celsius.

EXAMPLE 1 2-N-(Nα-Boc-D-tryptophanyl)amino-2'-fluorobenzophenone

2-Amino-2'-fluorobenzophenone (4 g, 18.6 mmole), Boc-D-tryptophan (5.65g, 18.6 mmole) and dicyclohexylcarbodiimide (DCC) (18.6 ml of a 1Msolution in methylene chloride, 18.6 mmole) were combined in 28 ml ofdry tetrahydrofuran stirred in an ice bath. The mixture was allowed towarm to room temperature and stirred overnight. The solids were removedby filtration and the filtrate evaporated in vacuo. The residue waschromatographed on 9" (23 cm) of silica gel (230-400 mesh) in a 55 mmdiameter column using 1 L of each of methylene chloride and 2% and 3%(v/v) diethyl ether in methylene chloride.

The product fractions were combined and evaPorated in vacuo. The residuewas crystallized from diethyl ether and the resulting solid dried invacuo at 40° for 20 hours: (m.p. 64°-67°).

The compound showed a single component by thin layer chromatography(TLC) (R_(f) =0.36, silica gel plate eluted with 6% (v/v) diethyl etherin methylene chloride). The NMR spectrum was consistent with the titlestructure and verifidd the presence of Et₂ O.

Anal. Calc'd for C₂₉ H₂₈ FN₃ O₄.Et₂ O: C, 68.85; H, 6.65; N, 7.30.Found: C, 69.25; H, 6.75; N, 7.30.

EXAMPLE 21,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazeoin-2-one

2-N-(N.sup.α -Boc-D-tryptophanyl)amino-2'-fluorobenzophenone (4.0 g=8.0mmole) in 37 ml of ethyl acetate was stirred in an ice bath andsaturated with hydrogen chloride gas for 20 minutes. The mixture wasevaporated to dryness in vacuo to give2-N-(D-tryptophanyl)amino-2'-fluorobenzophenonehydrochloride. Theresidue in 125 ml of methanol was treated with 30 ml of water and the pHof the mixture adjusted to 8.5-9.0 with 10% sodium hydroxide solution.The mixture was stirred at room temperature for three days.

The suspension was filtered and the resulting white solid dried in vacuoat 40° overnight: (m.p. 251°-254°).

The compound showed a single component by thin layer chromatography(TLC) (R_(f) =0.59, silica gel plate eluted with 1:1 (v/v) diethylether/methylene chloride) and by HPLC (greater than 99%). The NMRspectrum was consistent with the title structure. The mass spectrumshowed a molecular ion at m/e=383.

Anal. Calcd. for C₂₄ H₁₈ FN₃ O: C, 75.18; H, 4.73; N, 10.96. Found: C,74.88; H, 4.70, N, 10.65.

EXAMPLE 3 1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-b2H-1,4-benzodiazepin-2-one

2-Amino-2'-fluorobenzophenone (12.5 g=58 mmole) was stirred in 100 ml ofdry tetrahydrofuran in an ice bath. D-Tryptophan acid chloridehydrochloride (16 g=62 mmole), slurried in 50 ml of tetrahydrofuran, wasadded over 10 minutes, and the mixture stirred 2 hours in the ice bath.The resulting solid was filtered, then added to 200 ml of methanolcontaining 200 ml of water. The pH was adjusted to 8.5-9.0 with 10%sodium hydroxide, the mixture was stirred for three days, then filtered.The solid was dried in vacuo at 40°.

EXAMPLE 41,3-Dihydro-5-(2-fluorophenyl)-3(R)-[3'-(1'-methylindolyl)-methyl]-1-methyl-2H-1,4-benzodiazepin-2-one(A) and 1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-1-methyl-2H-1,4-benzodiazepin-2-one (B)

A:1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one(0.85 g, 2.2 mmole) and sodium hydride (0.11 g of a 50% suspension inmineral oil, 2.3 mmole) were stirred in 10 ml of dry, degasseddimethylformamide under nitrogen in an ice bath. After 40 minutes,methyl iodide (0.14 mL=2.25 mmole) was added in one portion. The mixturewas stirred for 1.5 hours at room temperature, then poured into 100 mlof water and extracted with methylene chloride (CH₂ Cl₂) (3×30 mL). TheCH₂ Cl₂ layers were washed with water, dried over potassium carbonate,filtered and evaporated in vacuo. The residue was chromatographed on 9"(23 cm) of silica gel (250-400 mesh) in a 55 mm diameter column elutedwith 4% (v/v) diethyl ether in CH₂ Cl₂. The first product eluted was Awhich was obtained as a glass upon evaporation. The solid was dried invacuo at room temperature: (m.p. 97°-100°()).

The compound showed a single component by thin layer chromatography(R_(f) =0.57, silica gel plate eluted with 10% (v/v) diethyl ether inCH₂ Cl₂) and by HPLC (98%). The NMR spectrum was consistent with thetitle structure and verified the presence of CH₂ Cl₂. The mass spectrumshowed a molecular ion at m/e=411.

Anal. Calc'd. for C₂₆ H₂₂ FN₃ O.0.1 CH₂ Cl₂ : C, 74.64; H, 5.33, N,10.01. Found: C, 74.69; H, 5.32; N, 9.63.

B: The second component eluted was the monomethyl compound B which wasobtained as a foam (0.66 g) upon evaporation. Crystallization fromhexane/CH₂ Cl₂ gave analytical material; (m.p. 80°-85°(↑)).

The compound showed a single component by thin layer chromatography(silica gel plates eluted with 4% (v/v) diethyl ether in CH₂ Cl₂) and byHPLC (99%). The NMR spectrum was consistent with the title structure andverified the presence of CH₂ Cl₂.

Anal. Calc'd for C₂₅ H₂₀ FN₃ O.0.75 CH₂ Cl₂ : C, 67.06, H, 4.70; N,9.11; Found: C, 67.04; H, 4.81; N, 9.14.

EXAMPLE 57-Chloro-1,3-dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

2-Amino-5-chlorobenzophenone (1.2 g, 5.2 mmole) and D-tryptophan methylester hydrochloride (1.3 g, 5.1 mmole) were combined in dry pyridine (25mL) and heated at reflux under nitrogen for 5 hrs. The mixture wasevaporated in vacuo and the residue washed twice with pH 6 buffer anddissolved in ethyl acetate (50 mL). The ethyl acetate solution was driedover sodium sulfate, filtered, and evaporated in vacuo to give an oilwhich was chromatographed on a 13 inch (33 cm) column of silica gel(230-400 mesh) in a 25 mm diameter column eluted with 20% (v/v) ethermethylene choride. The product fractions were evaporated in vacuo togive the title compound as a white solid which was dried in vacuo at100°: (m.p. 130°-155°(↑)).

The compound showed a single spot by thin layer chromatography (R_(f)=0.36, silica gel plate eluted with 4:1 CH₂ Cl₂ /ether) The NMR spectrumwas consistent with the title structure and verified the presence ofether. The compound was 99.8% pure by HPLC. The mass spectrum showed amolecular ion at m/e=399.

Anal. Calc'd for C₂₄ H₁₈ ClN₃ O.0.5C₄ H₁₀ O: C, 71.47; H, 5.31; N, 9.62;Cl, 8.12. Found C, 71.62; H, 5.83; N, 9.47; Cl, 8.24.

EXAMPLE 61,3-Dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using 2-aminobenzophenone(1.97 g, 0.01 mole), Boc-D-tryptophan (3.04 g, 0.01 mole) and DCC (10 mLof 1M solution in methylene chloride (CH₂ Cl₂) in THF (15 mL). The crudeproduct obtained after filtration and evaporation of the mixture wasdeprotected and cyclized by the procedure of Example 2. The mixture wasevaporated in vacuo, combined with water (50 mL) and extracted withchloroform (250 mL). The chloroform solution was hired over potassiumcarbonate, filtered, and evaporated to dryness in vacuo.Recrystallization from a mixture of acetone (50 mL) and ether (50 mL)gave a white solid which was dried in vacuo at 100°: (m.p.260°-263°(d)).

The compound showed a single spot by TLC (R_(f) =0.53, silica gl plateeluted with 1:1 CH₂ Cl₂ /ether) The NMR spectrum was consistent with thetitle structure and verified the presence of acetone. The compound was99.6% pure by HPLC. The mass spectrum showed a molecular ion at m/e=365.

Anal. Calc'd for C₂₄ H₁₉ N₃ O.0.5C₃ H₆ O: C, 77.64, H, 5.62, N, 10.65.Found: C, 77.34, H, 5.44, N, 10.87.

EXAMPLE 71,3-Dihydro-3(S)-[3'-(1'-methylindolyl)methyl]-1-methyl-5-methylthio-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3(S)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one-5-thione(450 mg, 1.4 mmole) was suspended in 30 ml of toluene, 8 ml oftetrahydrofuran, and 15 ml of 40% sodium hydroxide solution. Thismixture was treated with 203 mg (0.6 mmole) of tetra-n-butylammoniumsulfate and 0.25 ml (4.0 mmole) of iodomethane and stirred rapidly atroom temperature. After four hours the phases were separated and theaqueous layer extracted once with ethyl acetate. The combined organicextracts were washed with water (2×50 ml) and brine, then dried (MgSO₄)and concentrated in vacuo to afford a yellow oil. Preparative thicklayer chromatography (hexane-ethyl acetate 2:1 v/v) afforded the titlecompound as a white solid. R_(f) =0.45 (2:1 hexane-ethyl acetate). Theanalytical sample was recrystallized from ethyl acetate-ether, m.p. 170°C.; TLC, HPLC: 99% pure. Pmr (CDCl₃) according to theory (methyl protonresonate 2.46 ppm, 3.39 ppm, and 3.72 ppm respectively). MS (20 ev.):363 (M⁺), 184, 144.

Elemental Analysis: C₂₁ H₂₁ N₃ OS: Calc'd.: N, 11.56; C, 69.39; H, 5.82.Found: N, 11.47; C, 69.22; H, 6.04.

EXAMPLE 81,3-Dihydro-3(S)-(3'-indolyl)methyl-1-methyl-5-methylthio-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3(S)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one-5-thione(450 mg, 1.4 mmole) was suspended in 30 ml of toluene, 8 ml oftetrahydrofuran, and 15 ml of 40% sodium hydroxide solution. The mixturewas treated with 203 mg (0.6 mmole) of tetra-n-butylammonium sulfate and0.25 ml (4.0 mmole) of iodomethane and stirred rapidly at roomtemperature. After four hours the phases were separated and the aqueouslayer extracted once with ethyl acetate. The combined organic extractswere washed with water (2×50 ml) and brine, then dried (MgSO₄) andconcentrated in vacuo to afford a yellow oil. Preparative thick layerchromatography (hexane-ethyl acetate 2:1 v/v) afforded the titlecompound as a white solid. R_(f) =0.40 (2:1 hexane-ethyl acetate). Theanalytical sample was recrystallized from ethyl acetate-ether, m.p.90°-91° C. TLC, HPLC: 99% pure. Pmr (CDCl₃) according to theory (methylprotons resonate at 2.45 ppm and 3.40 ppm, respectively). MS (20 ev):349 (M⁺), 302, 220, 130.

Elemental Analysis: C₂₀ H₁₉ N₃ OS. Calc'd.: N, 12.02; C, 68.74; H, 5.48.Found: N, 12.10; C, 68.58; H, 5.71.

EXAMPLE 91,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-α-indolenyl)methyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one(120 mg, 0.31 mmole) was dissolved in 2 ml of trifluoroacetic acid. Theresulting orange solution was treated with 0.5 ml (3.1 mmole) oftriethylsilane and stirred rapidly at room temperature. After two hours,the reaction mixture was rotoevaporated to dryness and the residue waspartitioned between water/ethyl acetate. The organic phase was washedwith sodium bicarbonate solution (sat.), and brne, then dried (MgSO₄)and concentrated. The analytical sample was obtain via preparative thicklayer chromatography on silica gel (1:1 hexane-ethyl acetate v/v,multiple elutions).

R_(f) =0.38 (2:1 ethyl acetate-hexane).

Pmr (CDCl₃) in accord with theory.

MS (FAB): 386 (M+H).

Elemental Analysis: C₂₄ H₂₀ FN₃ O.0.4H₂ O: Calc'd.: N, 10.70; C, 73.41;H, 5.34. Found: N, 10.50; C, 73.62; H, 5.45.

EXAMPLE 10 1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-β-indolenyl)methyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one(120 mg 0.31 mmole) was dissolved in 2 ml of trifluoroacetic acid. Theresulting orange solution was treated with 0.5 ml (3.1 mmole) oftriethylsilane and stirred rapidly at room temperature. After two hours,the reaction mixture was rotoevaporated to dryness and the residue waspartitioned between water/ethyl acetate. The organic Phase was washedwith sodium bicarbonate solution (sat.), and brine, then dried (MgSO₄)and concentrated. The analytical sample was obtained via preparativethick layer chromatography on silica gel (1:1 hexane-ethyl acetate v/v,multiple elutions). R_(f) =0.30 (2:1 ethyl acetate-hexane). Pmr (CDCl₃)in accord with theory. MS (FAB): 386 (M+H).

Elemental Analysis: C₂₄ H₂₀ FB₃ O.0.3H₂ O: Calc'd.: N, 10.75; C, 73.75;H, 5.31. Found: N, 10.57; C, 73.86; H, 5.38.

EXAMPLE 111,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-thione

1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one(6.98 g, 18.20 mmole) was refluxed with 4.41 g (10.92 mmole) of2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane in100 ml of toluene for 1.5 hours. The solvent was removed in vacuo andthe residue partitioned between ethylacetate and 10% sodium hydroxidesolution. The organic phase was washed with 10% sodium hydroxide (3×50ml) and brine, then dried (MgSO₄) and rotoevaporated to give an orangeoil (10 g). Plug filtration of the crude product through silica gel (100g) afforded a solid which was recrystallized from ether to afford theanalytical sample. m.p. 147°-148° C.

Pmr: according to theory.

EXAMPLE 121,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin

To a solution of1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-thione(178 mg, 0.44 mmole) in 20 ml of absolute ethanol was added at roomtemperature one spatula of moist (ethanol) Raney-nickel catalyst(freshly prepared according to Fieser and Fieser, "Reagents for OrganicSynthesis", Vol. I, p. 729, John Wiley & Sons., Inc. N.Y., 1967). Theresulting suspension was protected from moisture and stirred rapidly forone hour. The reaction mixture was filtered and the filtrateconcentrated to give 150 mg of a yellow oil. Purification via silica gelchromatography (chloroform-methanol-ammonia 95:5:0.5 v/v) afforded theanalytical sample.

TLC, HPLC: confirmed purity.

MS (20 ev): 369 (M⁺), 239, 212, 130, 83.

Pmr (CDCl₃): according to theory.

Elemental Analysis: C₂₄ H₂₀ FN₃.0.07 CHCl₃. Calc'd.: N, 11.12; C, 76.52;H, 5.35. Found: N, 10.90; C, 76.66; H, 5.59.

EXAMPLE 137-Chloro-1,3-dihydro-3(R)-benzyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-5-chlorobenzophenone (2.32 gm, 0.01 mol), Boc-D-Phenylalanine(2.65 gm, 0.01 mol), and DCC (10 ml of 1.0 M solution in CH₂ Cl₂) in CH₂Cl₂ (10 ml). After filtration and evaporation, the crude solid wasdeprotected and cyclized by the procedure of Example 2. After stirring 5days, the mixture was evaporated in vacuo, treated with H₂ O (50 ml),and extracted with EtoAc (2×100 ml). The combined organic extracts werewashed with brine (50 ml), dried over MgSO₄, filtered and evaporated todryness in vacuo. Chromatogaphy on silica gel eluted with 7.5% (v/v) Et₂O in CH₂ Cl₂ gave a white foam which was crystallized from Et₂ O. Thesolid was dried in vacuo at 65° C.: (m.p. 154°-7° C.).

The compound showed a single spot by TLC (R_(f) =0.32, silica gel plateeluted with 10% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistentwith the title structure. The compound was 100% pure by HPLC.

Anal Calc.d for C₂₂ H₁₇ ClN₂ O: C, 73.23; H, 4.75; N, 7.76; Cl, 9.83.Found: C, 73.59; H, 4.78; N, 7.95; Cl, 10.03.

EXAMPLE 147-Chloro-1,3-dihydro-3(R)-(2-methyl-1-propyl)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-5-chlorobenzophenone (2.32 gm, 0.01 ml), Boc-D-Leucinemonohydrate (2.49 gm, 0.01 mol), and DCC (10 ml of 1.0 M solution in CH₂Cl₂) in CH₂ Cl₂ (25 ml). Filtration, concentration in vacuo andchromatography (silica gel, 5% (v/v) Et₂ O in CH₂ Cl₂) gave a yellow oilwhich was deprotected and cyclized by the procedure of Example 2. Afterstirring 48 h, the mixture was evaporated in vacuo, treated with H₂ O(50 ml), and extracted with EtOAc (2×200 ml). The combined organicextracts were washed with brine (50 ml), dried over MgSO₄, filtered, andevaporated to dryness in vacuo. Chromatography (silica gel, 7.5% (v/v)Et₂ O in CH₂ Cl₂) of the crude product gave a white foam which wascrystallized from Et₂ O. The solid was dried in vacuo at 65° C.: (m.p.156°-60° C.).

The compound showed a single spot by TLC (R_(f) =0.38, silica gel plate,10% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure. The compound was 100% pure by HPLC.

Anal. Calc'd for C₁₉ H₁₉ ClN₂ O: C, 69.82; H, 5.86; N, 8.57; Cl, 10.85.Found: C, 69.81; H, 5.84; N, 8.71; Cl, 11.20.

EXAMPLE 153(R)-Benzyloxymethyl-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-5-chlorobenzophenone (2.32 gm, 0.01 mol),N-Boc-O-Benzyl-D-serine (2.95 gm, 0.01 mol), and DCC (10 ml of 1.0 Msolution in CH₂ Cl₂) in CH₂ Cl₂ (10 ml). Filtration, concentration invacuo and chromatography (silica gel, CH₂ Cl₂) gave a colorless oilwhich was deprotected and cyclized by the procedure of Example 2. Afterstirring 5 days, the mixture was evaporated in vacuo, treated with H₂ O(50 ml), and extracted with EtOAc (2×100 ml). The combined organicextracts were washed with brine (50 ml), dried over MgSO₄, filtered, andevaporated to dryness in vacuo. Chromatography (silica gel, 75% (v/v)Et₂ O in CH₂ Cl₂) of the crude product gave a white foam which wascrystallized from Et₂ O. The solid was dried in vacuo at 65° C.: (m.p.113°-5° C.).

The compound showed a single spot by TLC (R_(f) =0.27, silica gel plate,10% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure and verified the presence of Et₂ O and H₂ O. Thecompound was 100% pure by HPLC.

Anal. Calc'd for C₂₃ H₁₉ ClN₂ O₂.0.1 C₄ H₁₀ O.0.25 H₂ O: C, 69.78; H,5.13; N, 6.96; Cl, 8.80. Found: C, 69.53; H, 5.17; N, 6.99; Cl, 8.98.

EXAMPLE 167-Chloro-1,3-dihydro-3(R)-(4-benzyloxybenzyl)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-5-chlorobenzophenone (2.32 gm, 0.01 mol),N-Boc-O-Benzyl-D-Tyrosine (3.71 gm, 0.01 mol), and DCC (10 ml of 1.0 Msolution in CH₂ Cl₂) in CH₂ Cl₂ (10 ml). After filtration andevaporation, the crude solid was deprotected and cyclized by theprocedure of Example 2. After stirring 5 days, the mixture wasevaporated in vacuo, treated with H₂ O (75 ml), and extracted with EtOAc(2×125 ml). The combined organic extracts were washed with brine (50ml), dried over MgSO₄, filtered, and evaporated to dryness in vacuo.Chromatography (silica gel, 7.5% (v/v) Et₂ O in CH₂ Cl₂) of the crudeproduct gave a white foam which was dried at 69° C. in vacuo: (m.p.97°-101° C.).

The compound showed a single spot by TLC (R_(f) =0.37, silica gel plate,10% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure. The compound was greater than 99.5% pure by HPLC.

Anal Cald'd for C₂₉ H₂₃ ClN₂ O₂ : C, 74.59; H, 4.97; N, 6.00. Found: C,74.52; H, 4.78; N, 6.01.

EXAMPLE 177-Chloro-1,3-dihydro-3(RS)-(1-naphthyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-5-chlorobenzophenone (845 mg, 3.65 mmol),N-Boc-α-DL-naphthylalanine (1.15 gm, 3.65 mmol), and DCC (3.65 ml of 1.0M solution in CH₂ Cl₂) in THF (5 ml). Filtration, concentration in vacuoand chromatography (silica gel, 1% (v/v) Et₂ O in CH₂ Cl₂) gave a lightyellow foam which was deprotected and cyclized by the procedure ofExample 2. After stirring 14 days, the mixture was evaporated in vacuo,treated with H₂ O (25 ml), and extracted with CH₂ Cl₂ (2×50 ml). Thecombined organic extracts were washed with brine (25 ml), dried overMgSO₄, filtered, and evaporated to dryness in vacuo. Chromatography(silica gel, 3% (v/v) Et₂ O in CH₂ Cl₂) of the crude product gave awhite foam which was crystallized from hexane. The solid was dried invacuo at 100° C.: (m.p. 180° -2° C.).

The compound showed a single spot by TLC (R_(f) =0.36, silica gel plate,10% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure. The compound was greater than 99.9% pure by HPLC.

Anal. Calc'd for C₂₆ H₁₉ ClN₂ O: C, 76.00; H, 4.66; H, 6.82; Cl, 8.63.Found: C, 75.99; H, 4.68; N, 6.65; Cl, 8.76.

EXAMPLE 187-Chloro-1,3-dihydro-3(RS)-(2-naphthyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-5-chlorobenzophenone (845 mg, 3.65 mmol),N-Boc-β-DL-naphthylalanine (1.15 gm, 3.65 mmol), and DCC (3.65 ml of 1.0M solution in CH₂ Cl₂) in THF (5 ml). Filtration, concentration in vacuoand chromatography (silica gel, 1% (v/v) Et₂ O in CH₂ Cl₂) gave a foamwhich was deprotected and cyclized by the procedue of Example 2. Afterstirring 24 hours, the mixture was evaporated in vacuo, treated with H₂O (25 ml), and extracted with EtOAc (2×50 ml). The combined organicextracts were washed with brine (25 ml), dried over MgSO₄, filtered, andevaporated to dryness in vacuo. Chromatography (silica gel, 5% (v/v) Et₂O in CH₂ Cl₂) of the crude product gave a foam which was crystallizedfrom Et₂ O/hexane. The solid was dried in vacuo at 100° C.: (m.p.140°-2° C.).

The compound showed a single spot by TLC (R_(f) =0.38, silica qel plate,10% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure. The compound was greater than 99.7% pure by HPLC.

Anal. Calc'd for C₂₆ H₁₉ ClN₂ O: C, 76.00; H, 4.66; N, 6.82; Cl, 8.63.Found: C, 75.77; H, 4.68; N, 6.77; Cl, 8.87.

EXAMPLE 191,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(2-thienyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-2'-fluorobenzophenone (1.26 gm, 5.86 mmol),N-Boc-β-(2-thienyl)-DL-alanine (1.75 gm, 6.45 mmol), and DCC (6.45 ml of1.0M solution in CH₂ Cl₂) in CH₂ Cl₂ (25 ml). Filtration, concentrationin vacuo and flash chromatography (silica gel, 1% (v/v) Et₂ O in CH₂Cl₂) gave a white foam which was deprotected and cyclized by theprocedure of Example 2. After stirring 3 days, the mixture wasevaporated in vacuo, treated with H₂ O (50 ml) and extracted with EtOAc(2×100 ml). The combined organic extracts were washed with brine (50ml), dried over MgSO₄, filtered, and evaporated to dryness in vacuo. Theresulting foam was crystallized from Et₂ O to give the title compound asa white solid. The solid was dried in vacuo at 65° C.: (m.p. 189°-91°C.).

The compound showed a single spot by TLC (R_(f) =0.54, silica gel plate,20% (v/v) Et₂ O in CH₂ Cl₂).

The NMR spectrum was consistent with the title structure. The compoundwas greater than 97.9% pure by HPLC.

Anal. Calc'd for C₂₀ H₁₅ FN₂ OS: C, 68.55; H, 4.32; N, 8.00. Found: C,68.74; H, 4.47; N, 8.02.

EXAMPLE 201,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(3-thienyl)-2H-1,4-benzodiazepin-2-one

The Procedure of Example 1 was carried out using2-amino-2'-fluorobenzophenone (1.59 g, 7.40 mmol),DL-α-Boc-amino-3-thiopheneacetic acid (2.0 gm, 7.77 mmol), and DCC (7.77ml of 1.0M solution in CH₂ Cl₂) in CH₂ Cl₂ (15 ml). Filtration,concentration in vacuo and chromatography (silica gel, 3% (v/v) Et₂ O inCH₂ Cl₂) gave a white foam which was deprotected (HCl/EtoAc, 00) andcyclized by heating (70° C. oil bath) in MeOH for 48 hours. The solventwas removed in vacuo and the residue crystallized from Et₂ O. Thecompound was dried in vacuo at 65° C.: (m.p. 219°-23° C.).

The compound showed a single spot by TLC (R_(f) =0.24, silica gel plate,30% (v/v) EtOAc in hexane). The NMR spectrum was consistent with thetitle structure. The compound was greater than 98.5% pure by HPLC.

Anal. Calc'd for C₁₉ H₁₃ FN₂ OS: C, 67.84; H, 3.90; N, 8.33. Found: C,67.75; H, 4.13; N, 7.98.

EXAMPLE 211,3-Dihydro-5-(2-fluorophenyl)-3(R)-[3'-β-(1'-t-Boc-L-leucyl)-indolenyl]methyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-β-indolenyl)methyl-2H-1,4-benzodiazepin-2-one(100 mg, 0.259 mmol), N-Boc-L-Leucine monohydrate (64.7 mg, 0.259 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 49.8mg, 0.259 mmol), and 1-hydroxybenzotriazole hydrate (HBT, 35.0 mg, 0.259mmol) were combined in freshly degassed dimethylformamide (DMF, 2 ml)and stirred at room temperature. The pH of the solution was adjusted to9.0-9.5 with triethylamine (0.108 ml, 0.777 mmol) and stirring wascontinued for 24 hours. The mixture was evaporated in vacuo, treatedwith 10% Na₂ CO₃ (aq) (20 ml) and extracted with EtOAc (2×30 ml). Thecombined extracts were washed with H₂ O (20 ml) and brine (20 ml), driedover MgSO₄, filtered, and evaporated to dryness in vacuo. The residuewas chromatographed (silica gel, 30% (v/v) EtOAc in hexane) to give thetitle compound as a foam. The foam was dried in vacuo at 65° C.: (m.p.118°-30° C.).

The compound showed a single spot by TLC (R_(f) =0.38, silica gel plate,40% (v/v) EtOAc in hexane). The NMR spectrum was consistent with thetitle structure and verified the presence of hexane. The compound wasgreater than 97% pure by HPLC. The mass spectrum showed a molecular ionat m/e=598.

Anal Calc'd for C₃₅ H₃₉ FN₄.1/3C₆ H₁₄ : C, 70.83; H, 7.02; N, 8.93.Found: C, 70.93; H, 6.88; N, 8.94.

EXAMPLE 221,3-Dihydro-5-(2-fluorophenyl)-3(R)-[3'-β-(1'-t-Boc-D-leucyl)-indolenyl]methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 21 was carried out using the same reagents andamounts except N-Boc-D-leucine monohydrate was substituted forN-Boc-L-leucine monohydrate. After 24 hours a second portion ofBoc-D-Leucine monohydrate (32 mg, 0.129 mmol), EDC (25 mg, 0.130 mmol),and HBT (17.5 mg; 0.130 mmol) was added and the pH readjusted to 9.0-9.5with Et₃ N. The reaction was worked up as in Example 21, and the titlecompound was obtained as a foam. This was dried in vacuo at 65° C.:(m.p. 135°-48° C.).

The compound showed a single spot by TLC (R_(f) =0.37, silica gel plate,40% (v/v) EtOAc in hexane). The NMR spectrum was consistent with thetitle structure. The compound was 87.5% pure by HPLC.

Anal Calc'd for C₃₅ H₃₉ FN₄ O₄ : C, 70.21; H, 6.57; N, 9.36. Found: C,70.25; H, 6.89; N, 9.53.

EXAMPLE 231,3-Dihydro-5-(2-fluorophenyl)-3(R)-[3'-α-(1'-t-Boc-L-leucyl)-indolenyl]methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 21 was carried out using the same reagents andquantities except 1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-α-indolenyl)methyl-2H-1,4-benzodiazepin-2-one was substituted for the 3'-β isomer.After 24 hours the reaction was worked up in the same manner and thetitle compound was obtained as a foam. This was dried in vacuo at 65°C.: (m.p. 130°-48° C.).

The compound showed a single spot by TLC (R_(f) =0.39, silica gel plate,40% (v/v) EtOAc in hexane). The NMR spectrum was consistent with thetitle compound. The compound was 91% pure by HPLC.

Anal. Calc'd for C₃₅ H₃₉ FN₄ O₄ : C, 70.21; H, 6.57; N, 9.36. Found: C,70.54; H, 6.98; N, 9.39.

EXAMPLE 241,3-Dihydro-5-(2-fluorophenyl)-3(R)-[3'-α-(1'-t-Boc-D-leucyl)-indolenyl]methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 23 was carried out using the same reagents andquantities except Boc-D-Leucine was substituted for Boc-L-Leucine. After24 hours the reaction was worked up in the same manner and the titlecompound was obtained as a white foam. This was dried in vacuo at 65°C.: (m.p. 130°-145° C.).

The compound showed a single spot by TLC (R_(f) =0.39, silica gel plate,40% (v/v) EtOAc in hexane). The NMR spectrum was consistent with thetitle structure. The compound was 95.1% pure by HPLC.

Anal. Cald'd for C₃₅ H₃₉ FN₄ O₄ : C, 70.21; H, 6.57; N, 9.36. Found: C,70.31; H, 6.81; N, 9.67.

EXAMPLE 257-Chloro-1,3,4,5-tetrahydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

7-Chloro-1,3,dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneetherate (240 mg, 0.506 mmol) was dissolved in acetic acid (10 ml) andcooled to 10° C. To the yellow solution was added sodiumcyanoborohydride (63.6 mg, 1.01 mmol) all at once. After stirring 15minutes at 10° C., the reaction was diluted with H₂ O (10 ml), basifiedwith sat'd Na₂ CO₃ (aq.), and extracted with EtOAc (2×25 ml). Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered, and evaporated to dryness in vacuo. The residue waschromatographed (silica gel, 900/10/1/1 (v/v/v/v) of CH₂ Cl₂ /MeOH/H₂O/HoAc) and the product fractions evaporated to dryness in vacuo. Theresidue was dissolved in absolute ethanol, filtered, and treated with5.37 M HCl in ethanol until the solution was acidic. The productcrystallized as fine white needles which were dried in vacuo at 82° C.:(m.p. 198°-204° C.).

The compound showed a single spot by TLC (R_(f) =0.35, silica gel plate,300/10/1/1 (v/v/v/v) CH₂ Cl₂ /MeOH/H₂ O/HoAc). The NMR spectrum wasconsistent with the title structure and verified the presence of H₂ O.The mass spectrum showed a molecular ion at m/e=401.

Anal. Calc'd for C₂₄ H₂₀ ClN₃ O.HCl.0.75H₂ O: C, 63.79; H, 5.02; N,9.30; Cl, 15.69. Found: C, 63.59; H, 4.94; N, 9.39; Cl, 15.32.

EXAMPLE 267-Chloro-1,3,4,5-tetrahydro-3(S)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

7-Chloro-1,3-dihydro-3(S)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(300 mg, 0.750 mmol) was dissolved in acetic acid (10 ml) and cooled to10° C. To the yellow solution was added sodium cyanoborohydride (63.6mg, 1.01 mmol) all at once. After stirring 15 minutes at 10° C., thereaction was diluted with H₂ O (10 ml), basified with sat'd Na₂ CO₃(aq.), and extracted with EtOAc (2×25 ml). The combined organic extractswere washed with brine (10 ml), dried over MgSO₄, filtered, andevaporated to dryness in vacuo. The crude residue was dissolved inabsolute ethanol (3 ml), filtered, and treated with 5.37M ethanolic HCluntil the solution was acidic. The product crystallized as fine whiteneedles which were dried in vacuo at 82° C.: (m.p. 198°-204° C.).

The compound showed a single spot by TLC (R_(f) =0.30, silica gel plate,300/10/1/1 (v/v/v/v) of CH₂ Cl₂ /MeOH/H₂ O/HoAc). The NMR spectrum wasconsistent with the title structure and verified the presence of H₂ Oand ethanol.

Anal. Calc'd for C₂₄ H₂₀ ClN₃ O.HCl.0.5H₂ O.0.25C₂ H₅ OH: C, 64.12; H,5.16; N, 9.16; Cl, 15.45. Found: C, 63.91; H, 5.02; N, 9.01; Cl, 15.36.

EXAMPLE 274-(p-Chlorobenzoyl)-5-(2-fluorophenyl)-3(R)-[3'-(1'-methylindolyl)-methyl]-1-methyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one(A) and4-acetyl-5-(2-fluorophenyl)-3(R)-[3'-(1'-methylindolyl)-methyl]-1-methyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one(B)

The procedure of Example 25 was carried out using1,3-dihydro-5-(2-fluorophenyl)-3(R)-[3'-(1'-methylindolyl)-methyl]-1-methyl-2H-1,4-benzodiazepin-2-one(1.0 gm, 2.43 mmol) and sodium cyanoborohydride (305 mg, 4.86 mmol) inglacial acetic acid (4 ml). The crude reduction product obtained uponevaporation of the EtOAc extracts was used without further purification.

A: The crude reduction product (200 mg, 0.484 mmol) was partitionedbetween CH₂ Cl₂ (6 ml) and H₂ O (5 ml) and cooled to 0° C. 1N NaOH (0.73ml) was added, followed by p-chlorobenzoyl chloride (0.092 ml, 0.726mmol). After 24 hours at ambient temperature, a second portion of 1NNaOH (0.50 ml) and p-chlorobenzoyl chloride (0.045 ml, 0.354 mmol) wasadded, and after 24 hours a third portion of 1N NaOH (50 ml) andp-chlorobenzoylchloride (0.045 ml, 0.354 mmol) was added. After another24 hours, the mixture was extracted with CH₂ Cl₂ (3×10 ml). The combinedorganic layers were washed with 10% NaHCO₃ (10 ml), H₂ O (10 ml), andbrine (10 ml), dried over MgSO₄, filtered, and evaporated in vacuo.Chromatography (silica gel, 5% (v/v) Et₂ O in CH₂ Cl₂) of the cruderesidue gave a foam which was crystallized from Et₂ O. The compound wasdried in vacuo at 78° C.: (m.p. 237°-43° C.).

Anal. Calc'd for C₃₃ H₂₇ FClN₃ O₂.0.05 Et₂ O: C, 71.75; H, 4.99; N,7.56; Cl, 6.38. Found: C, 71.84; H, 5.28; N, 7.92; Cl, 6.63.

The compound showed a single spot by TLC (R_(f) =0.50, silica gel plate,4% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure and erified the presence of Et₂ O. The compound wasgreater than 99% pure by HPLC.

B: The crude reduction product (200 mg, 0.484 mmol) was dissolved in CH₂Cl₂ (10 ml) and 3 portions of acetyl chloride (each 0.026 ml, 0.363mmol) and triethylamine (0.35 ml, 0.363 mmol) were added at 3 hourintervals. Water (2 ml) was then added and the mixture was extractedwith CH₂ Cl₂ (3×10 ml). The combined organic layers, were washed with10% Na₂ CO₃ (aq.) (10 ml), H₂ O (10 ml) and brine (10 ml), dried overMgSO₄, filtered, and evaporated in vacuo. Chromatography (silica gel, 5%(v/v) Et₂ O in CH₂ Cl₂) of the crude residue gave a white foam which wascrystallized from Et₂ O. The compound was dried in vacuo at 78° C.:(m.p. 214°-216.5° C.).

The compound showed a single spot by TLC (R_(f) =0.41, silica gel plate,15% (v/v) Et₂ O in the title structure. The compound was greater than99.5% pure by HPLC. The mass spectrum showed a molecular ion at m/e=455.

Anal. Calc'd for C₂₈ H₂₆ FN₃ O₂ : C, 73.82; H, 5.75; N, 9.23. Found: C,73.62; H, 5.93; N, 9.22.

EXAMPLE 287-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using2-amino-2',5-dichlorobenzophenone (2.66 g, 0.01 mole), Boc-D-tryptophan(3.04 g, 0.01 mole), and DCC (10 ml of 1 M solution in methylenechloride) in THF (15 ml). The crude product obtained after filtrationand evaporation of the mixture was chromatographed on silica gel(230-400 mesh, 9 inch (23 cm) column 55 mm diameter), using methylenechloride followed by 5% (v/v) ether/methylene chloride. The productfractions were evaporated in vacuo to give the product as a foam. Thismaterial was deprotected and cyclized using the procedure of Example 2.The cyclization in this case required 15 days. At the end of this timethe mixture was evaporated in vacuo, treated with water (10 ml), andextracted with methylene chloride (3×50 ml). The methylene chloridelayers were dried over potassium carbonate, filtered, and evaporated invacuo to give the crude product as a foam. This material waschromatographed on silica gel (230-400 mesh, 8 inch (20 cm) column, 25mm diameter, elution with methylene chloride followed by 10% (v/v)ether/methylene chloride). The product fractions were evaporated invacuo and the residue crystallized from ether by addition ofcyclohexane. The title compound was obtained as a white solid which wasdried in vacuo at 80°: (mp 140°-170° (d)).

The compound showed a single spot by TLC (R_(f) =0.61, silica gel plateeluted with 1:1 (v/v) ether/methylene chloride). The NMR spectrum wasconsistent with the title structure. The mass spectrum showed amolecular ion at m/e=433. The compound was 98% pure by HPLC.

Analysis Calc'd for C₂₄ H₁₇ Cl₂ N₃ O: C, 66.37; H, 3.94; N, 9.68; Found:C, 66.70; H, 4.05; N, 9.61.

EXAMPLE 291,3-Dihydro-3(R)-(3'-indolyl)methyl-5-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using 2-aminobenzophenone(1.35 g, 0.01 mole), Boc-D-tryptophan (3.04 g, 0.01 mole), and DCC (10ml of lM solution in methylene chloride) in THF (15 ml). The mixture wasfiltered, evaporated in vacuo and the residue chromatographed on silicagel (230-400 mesh, 9 inch (23 cm) column, 55 mm diameter) eluted withmethylene chloride followed by 5%, 71/2% and 8% (v/v) ether/methylenechloride. The product fractions were evaporated in vacuo and the residuewas deprotected and cyclized by the procedure of Example 2. Thecyclization required seven days. The mixture was evaporated in vacuo andpartitioned between water and methylene chloride. The methylene chloridelayers were washed twice with water, dried over magnesium sulfate,filtered and evaporated in vacuo. The residue was chromatographed onsilica gel (230-400 mesh, 11 inch (28 cm) column, 25 mm diameter, 1:1and 2:1 (v/v) ether/methylene chloride elution). The product fractionswere evaporated in vacuo to provide the title compound: (mp 185°-190°).The compound was dried in vacuum at 100° overnight.

The compound showed a single spot by TLC (R_(f) =0.29, silica gel plateeluted with 1:1 (v/v) ether/methylene chloride). The NMR spectrum wasconsistent with the title structure. The mass spectrum showed amolecular ion at m/e=303. The compound was 95.6% pure by HPLC.

Analysis Calc'd for: C₁₉ H₁₇ N₃ O.0.1H₂ O: C, 74.78; H, 5.68; N, 13.78;Found: C, 74.60; H, 6.06; N, 13.74.

EXAMPLE 30 1-Benzyl-7-chloro-1,3-dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using7-chloro-1,3-dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneetherate (0.1 g, 0.22 mmole) in place of1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one,and 50% sodium hydride in mineral oil (0.015 g, 0.31 mmole) in dry DMF(2 ml). In place of methyl iodide, benzyl bromide (0.058 g, 0.34 mmole)was added to the mixture. Chromatography on a 6 inch (15 cm), 15 mmdiameter silica gel column with 5% (v/v) ether/methylene chlorideelution and evaporation of the product fractions gave a residue whichwas recrystallized from cyclohexane to provide the title compound whichwas dried in vacuo at 60°: (mp ca. 80° (indistinct)).

The compound showed a single spot by TLC (R_(f) =0.66, silica gel plateeluted with 10% (v/v) ether/methylene chloride). The NMR spectrum wasconsistent with the title structure and verified the presence ofapproximately 1/2 mole of cyclohexane. The compound was 100% pure byHPLC. The mass spectrum showed a molecular ion at m/e=489.

Analysis Calc'd for: C₃₁ H₂₄ ClN₃ O.0.5C₆ H₁₂ : C, 76.74; H, 5.68; N,7.90; Cl, 6.66; Found: C, 76.83; H, 5.71; N, 7.79; Cl, 6.72.

EXAMPLE 317-Chloro-1,3-Dihydro-3(R)-(3'-indolyl)methyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using7-chloro-1,3-dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneetherate (0.1 g, 0.22 mmole) in place of1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one,50% sodium hydride in mineral oil (0.014 g, 0.29 mmole), and methyliodide (0.045 g, 0.32 mmole) in DMF (2 ml). Chromatography on a six inch(15 cm), 15 mm diameter silica gel column provide the title compoundwhich, after evaporation and in vacuo, was dissolved in acetone,precipitated with water and filtered. The resulting solid was dried invacuo at 70°:(mp 134°-152° (indistinct)).

The compound showed a single spot by TLC (R_(f) =0.22, silica gel plateeluted with 5% (v/v) ether/methylene chloride. The NMR spectrum wasconsistent with the title structure. The compound was 98.9% pure byHPLC. The mass spectrum showed a molecular ion at m/e=413.

Analysis Calc'd for: C₂₅ H₂₀ ClN₃ O: C, 72.54; H, 4.87; N, 10.15; Cl,8.57; Found: C, 72.38; H, 4.88, N, 10.20; Cl, 8.32.

EXAMPLE 32 1,3-Dihydro-5-(2-fluorophenyl)-3(S)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 1 was carried out using 0.7 g (3.25 mmole) of2-amino-2'-fluorobenzophenone, 0.99 g, (3.25 mmole) of Boc-L-tryptophan,and 3.25 ml (3.25 mmole) of 1M DCC/CH₂ Cl₂ in 5 ml of THF. The productobtained by silica gel chromatography (10 inch (25 cm) column, 25 mmdiameter, methylene chloride and 2% and 3% (v/v) ether/methylenechloride elution) was deprotected and cyclized according to theprocedure of Example 2. The cyclization required three days. Theresulting mixture was evaporated in vacuo, partitioned between water andmethylene chloride, and separated. The aqueous layer was extracted twicewith methylene chloride, and the combined methylene chloride layers werewashed with water, dried over sodium sulfate, filtered, and evaporatedin vacuo. The residue was recrystallized from acetone/ether, and theresulting solid dried in vacuo at 100°: (mp 255°-257°).

The compound showed a single component by TLC (R_(f) =0.59, silica gelplate eluted with 1:1 (v/v) methylene chloride/ether. The NMR spectrumwas consistent with the title structure. The mass spectrum showed amolecular ion at m/e=383. The compound was 99.3% pure by HPLC.

Analysis Calc'd for C₂₄ H₁₈ FN₃ O: C, 75.18; H, 4.73; N, 10.96; Found:C, 75.45; H, 4.71; N, 11.11.

EXAMPLE 33 1-Benzyl-7-chloro-1,3-dihydro-3(S)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using7-chloro-1,3-dihydro-3(S)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneetherate (0.1 g, 0.22 mmole) in place of1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one,50% sodium hydride in mineral oil (0.014 g, 0.29 mmole), and benzylbromide (0.058 g, 0.34 mmole) in place of methyl iodide. The reactionwas run in 1.5 ml of dry DMF. Silica gel chromatography (8 inch (20 cm)column, 15 mm diameter, methylene chloride and 5% (v/v) ether/methylenechloride elution)) and evaporation of the product fractions in vacuogave the title compound which was dried in vacuo at 60°: (mp 80°-120°(indistinct)).

The compound showed a single component by TLC (R_(f) =0.40, silica gelplate eluted with 5% (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure and showed 1/2 mole ofcyclohexane. The compound was 99.3% pure by HPLC. The mass spectrumshowed a molecular ion at m/e=489.

Analysis Calc'd for C₃₁ H₂₄ ClN₃ O.1/2C₆ H₁₂ : C, 76.74; H, 5.68; N,7.90; Cl, 6.66; Found: C, 76.56; H, 5.67; N, 7.86; Cl, 7.00.

EXAMPLE 347-Chloro-1,3-dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-thione

7-Chloro-1,3-dihydro-3(R)-(3'-indolyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneetherate (1.0 g, 2.1 mmole) and P₂ S₅ (0.51 g, 2.3 mmole) were combinedin dry pyridine (16 ml) and heated at reflux for 40 minutes. Pyridinewas removed by evaporation in vacuo and the residue treated with icewater and extracted with methylene chloride. The methylene chloridelayers were combined, dried over potassium carbonate, filtered, andevaporated in vacuo to give a foam. This material was chromatographed onsilica gel (9 inch (23 cm) column, 25 mm diameter, 15% (v/v)ether/methylene chloride elution), and the product fractions evaporated.The residue was recrystallized from acetone/ethyl acetate and the soliddried in vacuo at 90°: (mp 279°-280°).

The compound showed a single spot by thin layer chromatography (R_(f)=0.32, silica gel plate eluted with 10% (v/v) ether/methylene chloride).The NMR spectrum was consistent with the title structure. The compoundwas 98.6% pure by HPLC. The mass spectrum showed a molecular ion atm/e=415.

Analysis Calc'd for C₂₄ H₁₈ ClN₃ S: C, 69.30; H, 4.36; N, 10.10; S,7.71; Found: C, 69.39; H, 4.39; N, 10.14; S, 7.46.

EXAMPLE 351,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-[N'-(3-thienoyl)]hydrazide

1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-thione(0.28 g, 0.7 mmole) and 3-thienoyl chloride (0.1 g, 0.7 mmole) werecombined in ether (5 ml) and THF (1 ml) and stirred at room temperature.After one hour the mixture was filtered and evaporated in vacuo, and theresidue chromatographed on silica gel (8 inch (20 cm) column, 25 mmdiameter, 11/2% followed by 3% (v/v) methanol/methylene chlorideelution). The product fractions were evaporated in vacuo and theresulting solid dried in vacuo at 70°: (mp 207°-209°( )).

The compound showed a single spot by TLC (R_(f) =0.4, silica gel plateeluted with 5% (v/v) methanol/methylene chloride). The NMR spectrum wasconsistent with the title structure. The compound was 92% pure by HPLC.

Analysis Calc'd for C₂₉ H₂₂ FN₅ OS.0.2H₂ O: C, 68.13; H, 4.42; N, 13.70;Found: C, 68.19; H, 4.30; N, 13.91.

EXAMPLE 361,3-Dihydro-1-ethyl-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using ethyl iodide (0.35 g,2.25 mmole) in place of methyl iodide. Silica gel chromatographyfollowed by evaporation in vacuo gave the product which was dried atroom temperature in vacuo (mp 95°-113°).

The compound showed a single spot by thin layer chromatography (R_(f)=0.44, silica gel plate eluted with 10% (v/v) ether/methylene chloride).The NMR spectrum was consistent with the title structure and showed thepresence of approximately 0.15 mole of methylene chloride. The compoundwas 95.3% pure by HPLC. The mass spectrum showed a molecular ion atme=411.

Analysis Calc'd for: C₂₆ H₂₂ FN₃ O.0.15CH₂ Cl₂ : C, 74.04; H, 5.30; N,9.91; Found: C, 74.17; H, 5.22; N, 10.02.

EXAMPLE 371-Cyclopropylmethyl-1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out usingcyclopropylmethylbromide (0.30 g, 2.25 mmole) in place of methyl iodide.The product obtained by chromatography and evaporation wasrecrystallized from a mixture of methylene, chloride, ether, and hexane,and the resulting solid dried in vacuo at 80°: (mp 207.5°-208.5°).

The compound showed a single component by TLC (R_(f) =0.26, silica gelplate eluted with 4% (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure. The compound was 99.6% pure byHPLC. The mass spectrum showed a molecular ion at m/e=437.

Analysis Calc'd for C₂₈ H₂₄ FN₃ O.0.07CH₂ Cl₂ : C, 76.02; H, 5.49; N,9.48; Found: C, 75.96; H, 5.42; N, 9.30.

EXAMPLE 38 1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-1-pentyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using 1-bromopentane (0.34 g,2.25 mmole) in place of methyl iodide. The product obtained after silicagel chromatography and evaporation was crystallized from ether and driedin vacuo at 80°: (mp 150°-151°).

The compound showed a single component by thin layer chromatography(R_(f) =0.37, silica gel plate eluted with 4% (v/v) ether/methylenechloride). The NMR spectrum was consistent with the title structure. Thecompound was 99.9% pure by HPLC. The mass spectrum showed a molecularion at me=453.

Analysis Calc'd for: C₂₉ H₂₈ FN₃ O: C, 76.79; H, 6.22; N, 9.26; Found:C, 76.64; H, 6.39; N, 8.83.

EXAMPLE 39 1,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-1-(3-methylbutyl)-2H-1,4-benzodiazepine-2-one

The procedure of Example 4 was carried out using 1-bromo-3-methylbutane(0.34 g, 2.25 mmole) in place of methyl iodide. The product obtainedafter silica gel chromatography and evaporation was crystallized fromether and dried in vacuo at 80°: (mp=198°-199.5°).

The compound showed a single component by thin layer chromatography(R_(f) =0.30, silica gel plate eluted with 4% (v/v) ether/methylenechloride). The NMR spectrum was consistent with the title structure andshowed the presence of 0.2 mole of ether. The compound was 99.9% pure byHPLC. The mass spectrum showed a molecular ion at m/e=453.

Analysis Calc'd for: C₂₉ H₂₈ FN₃ O.0.2C₄ H₁₀ O: C, 76.42; H, 6.46; N,8.97; Found: C, 76.52; H, 6.38; N, 9.01.

EXAMPLE 401,3-Dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-1-(2,2,2-trifluoroethyl)-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using 2,2,2-trifluoroethyliodide (0.47 g, 2.25 mmole) in place of methyl iodide. Followingaddition of the trifluoroethyl iodide, the reaction was heated for 18hours in an oil bath thermostatted at 65°. Workup and chromatography asdescribed in Example 4 gave a product which was recrystallized fromether and dried in vacuo at 80°: (mp 189°-192°).

The compound showed a single component by thin layer chromatography(R_(f) =0.50, silica gel plate eluted with 5% (v/v) ether/methylenechloride). The NMR spectrum was consistent with the title structure. Thecompound was 99.2% pure by HPLC. The mass spectrum showed a molecularion at m/e=465.

Analysis Calc'd for: C₂₆ H₁₉ F₄ N₃ O: C, 67.09; H, 4.11; N, 9.03; Found:C, 67.32; H, 4.31; N, 8.98.

EXAMPLE 41 1,3-Dihydro-1-(2-dimethylaminoethyl)-5-(2-fluorophenyl)3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using1-chloro-2-(dimethylamino)propane (0.24 g, 2.25 mmole) in place ofmethyl iodide. Following addition of the chloride, the reaction wasstirred at room temperature for 5 days and then worked up as describedin Example 4. The chromatographed product was crystallized frommethylene chloride/hexane and the resulting solid dried in vacuo at 80°:(mp 200°-201°).

The compound showed a single component by TLC (R_(f) =0.30, silica gelplate eluted with 5% (v/v) methanol/methylene chloride). The NMRspectrum was consistent with the title structure. The compound was 99.6%pure by HPLC. The mass spectrum showed a molecular ion at m/e=454.

Analysis Calc'd for: C₂₈ H₂₇ FN₄ O: C, 73.98; H, 5.99; N, 12.33; Found:C, 73.92; H, 6.00; N, 11.28.

EXAMPLE 421,3-Dihydro-1-(ethoxycarbonylmethyl)-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using ethyl bromoacetate(0.38 g, 2.25 mmole) in place of methyl iodide. The chromatographedproduct was evaporated and dried in vacuo at room temperature: (mp88°-100°).

The compound showed a single component by TLC (R_(f) =0.42, silica gelplate eluted with 10% (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure and showed the presence of 0.24mole of methylene chloride. The compound was 92.6% pure by HPLC. Themass spectrum showed a molecular ion at m/e=469.

Analysis Calc'd for C₂₈ H₂₄ FN₃ O₃.0.24CH₂ Cl₂ : C, 69.23; H, 5.04; N,8.58; Found: C, 69.14; H, 5.09; N, 8.87.

EXAMPLE 431-Carboxymethyl-1,3-dihydro-5-(2-fluorophenyl)-3(R)-3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-1-(ethoxycarbonylmethylene)-5-(2-fluorophenyl)-3(R)-(3-indolyl)methyl-2H-1,4-benzodiazepin-2-one (83.2 mg, 0.177 mmole), and 1molar sodium hydroxide (0.18 ml, 0.18 mmole) were combined in 1 ml ofmethanol and stirred at room temperature for 24 hours. The solution wasacidified with 1 molar hydrochloric acid, and the mixture evaporated invacuo. The residue was taken up in methylene chloride, wahed with water,dried over sodium sulfate, filtered, and evaporated in vacuo to dryness.The residue was triturated with ether followed by petroleum ether, andfiltered to give the product which was dried in vacuo at 80°; (mp175°-180°(C)).

The compound showed a single component by TLC (R_(f) =0.52, silica gelplate eluted with 90:10:1:1 (v/v/v/v) methylene chloride/methanol/aceticacid/water). The NMR spectrum was consistent with the title structureand showed the presence of both ether and hexane. The compound was 97.2%pure by HPLC. The mass spectrum showed a molecular ion at m/e=441.

Analysis Calc'd for C₂₆ H₂₀ FN₃ O.0.1C₄ H₁₀ O.0.04C₆ H₁₄.H₂ O: C, 68.02;H, 5.05; N, 8.94; Found: C, 67.91; H, 5.04; N, 8.92.

EXAMPLE 441,3-Dihydro-5-(2-fluorophenyl)-3(R)-[3'-(1'-methylindolyl)methyl]-1-methyl-2H-1,4-benzodiazepin-2-one

The method of Example 4 was employed except that the starting materialwas1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-1-methyl-2H-1,4-benzodiazepin-2-one(1.3 g, 3.3 mmole). Fifty percent sodium hydride in mineral oil (0.16 g,3.3 mmole) and methyl iodide (0.47 g, 3.3 mmole) were employed in 10 mlof dry DMF. Following workup and chromatography as in Example 4, theproduct was obtained having physical properties identical to thosereported in Example 4.

EXAMPLE 451,3-Dihydro-5-(2-fluorophenyl)-3(R)-[3'-(1'-p-chlorobenzyloylindolyl)methyl]-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-1-methyl-2H-1,4-benzodiazepin-2-one(0.345 g, 0.87 mmole) in place of1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one,and p-chlorobenzoyl chloride (0.26 g, 1.5 mmole) in place of methyliodide. The reaction, employing 0.047 g (0.97 mmole) of 50% sodiumhydride in mineral oil, was carried out in 10 ml of dry DMF. Silica gelchromatography as described in Example 4, followed by evaporation invacuo and trituration with hexane, gave a solid which was dried in vacuoat 50°: (mp 75°(C)).

The compound showed a single component by TLC (R_(f) =0.57, silica gelplate eluted with 4% (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure and verified the presence ofapproximately 0.3 mole of hexane. The compound was 99.3% pure by HPLC.

Analysis Calc'd for C₃₂ H₂₃ FClN₃ O.0.3C₆ H₁₄ : C, 72.25; H, 4.88; N,7.48; Cl, 6.31; Found: C, 72.42; H, 5.02; N, 7.50; Cl, 6.55.

EXAMPLE 467-Chloro-1,3-dihydro-3(R)-[3'(1'-benzylindolyl)methyl]1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 45 was carried out using 0.042 g (0.88 mmole)of 50% sodium hydride, and benzylbromide (0.16 g, 0.92 mmole) in placeof p-chlorobenzoyl chloride. Reaction was conducted in 4 ml of dry DMF.Following silica gel chromatography and evaporation, the product wasrecrystallized from cyclohexane and dried in vacuo at 60°: (mp77°-80°(indistinct)).

The compound showed a single component by TLC (R_(f) =0.59, silica gelplate eluted with 5% (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure and showed the presence of 1/3mole of cyclohexane. The compound was 98.7% pure by HPLC. The massspectrum showed a molecular ion at m/e=503.

Analysis Calc'd for C₃₂ H₂₆ ClN₃ O.1/3C₆ H₁₂ : C, 76.75; H, 5.68; N,7.90; Cl, 6.66; Found: C, 76.50; H, 5.74; N, 7.59; Cl, 6.90.

EXAMPLE 471,3-Dihydro-3(RS)-[1-hydroxy-1-(3'-indolyl)]methyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The lithium salt of1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (1.25 g, 5mmole) was made according to the procedure of J. Org. Chem. 46, 3945(1981) using 1.01 g (10 mmole) of diisopropylamine, and 6.7 ml of a 1.5molar solution (10 mmole) of n-butylithium in hexane. This anionsolution was added by syringe to a solution of 0.725 g (5 mmole) ofindole-3-carboxaldehyde in 15 ml of dry THF stirred under nitrogen in adry ice-acetone bath. The mixture was warmed to room temperature,stirred for 11/2 hours and then quenched by the addition of saturatedsodium chloride solution. The mixture was separated and the aqueouslayer extracted twice with methylene chloride (2×10 ml). The organiclayers were dried over sodium sulfate, filtered and evaporated todryness in vacuo. The residue was chromatographed on silica gel (230-400mesh, 8 inch (20 cm) column, 25 mm diameter, 1:1 ether/methylenechloride elution). The evaporated product fractions were crystallizedfrom ether and dried in vacuo at 70°: (mp 218°-221°).

The compound showed a single component by TLC (R_(f) =0.30, silica gelplate eluted with 1:1 (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure. The compound was 90% pure byHPLC. The mass spectrum showed a molecular ion at me=395.

Analysis Calc'd for C₂₅ H₂₁ N₃ O₂.0.25H₂ O: C, 75.07; H, 5.42; N, 10.51;Found: C, 75.04; H, 5.50; N, 10.59.

EXAMPLE 481,3-Dihydro-1-methyl-5-phenyl-3-(RS)-(3-thienoyl)-2H-1,4-benzodiazepin-2-one

The procedure of Example 47 was carried out using thiophene-3-carbonylchloride (730 mg, 5.0 mmol) in place of indole-3-carboxaldehyde.Following chromatography (silica gel, 5% (v/v) Et₂ O in CH₂ Cl₂), theproduct was evaporated to dryness and crystallized from Et₂ O. The solidwas dried in vacuo at 65° C.: (m.p. 205°-8° C.).

The compound showed a single spot by TLC (R_(f) =0.54, silica gel plate,10% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure. The compound was greater than 92.4% pure by HPLC. Themass spectrum showed a molecular ion at m/e=360.

Anal. Calc'd for C₂₁ H₁₆ N₂ O₂ S: C, 69.98; H, 4.47; N, 7.77. Found: C,70.27; H, 4.64; N, 7.69.

EXAMPLE 491,3-Dihydro-3-(RS)-[1-hydroxy-1-(3-thienyl)]methyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 47 was carried out usingthiophene-3-carboxaldehyde (560 mg, 5.0 mmol) in place ofindole-3-carboxaldehyde. Following chromatography (silica gel, 15% (v/v)Et₂ O in CH₂ Cl₂), the product was evaporated to dryness andcrystallized from Et₂ O. The solid was dried in vacuo at 65° C.: (m.p.189°-91° C.).

The compound showed a single spot by TLC (R_(f) =0.36, silica gel plate,15% (v/v) Et₂ O in CH₂ Cl₂). The NMR spectrum was consistent with thetitle structure. The compound was greater than 99.0% pure by HPLC. Themass spectrum showed a molecular ion at m/e=362.

Anal. Calc'd for C₂₁ H₁₈ N₂ O₂ S: C, 69.59; H, 5.01; N, 7.73. Found: C,69.62; H, 5.01; N, 7.57.

EXAMPLE 501,3-Dihydro-3(RS)-[1-hydroxy-1-[3-(1-methylindolyl)]]-methyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(two stereoisomers, A and B)

The procedure of Example 47 was carried out using1-methylindole-3-carboxaldehyde (797 mg, 5.0 mmol) in place ofindole-3-carboxaldehyde. The product diastereomers were separated bychromatography (silica gel, 10% (v/v) Et₂ O in CH₂ Cl₂) and evaporatedto dryness.

A: The faster running component (TLC-R_(f) =0.41, silica gel plate, 60%(v/v) EtOAc in hexane) was crystallized from Et₂ O. The solid was driedin vacuo at 65° C.: (m.p. 218°-21° C.).

The compound showed a single spot by TLC. The NMR spectrum wasconsistent with the title structure. The compound was greater than 96.7%pure by HPLC. The mass spectrum showed a molecular ion at m/e=409.

Anal. Calc'd for C₂₆ H₂₃ N₃ O₂ : C, 76.26; H, 5.66; N, 10.26. Found: C,76.26; H, 5.84; H, 10.34.

B: The slower running component (TLC-R_(f) =0.30, silica gel plate, 60%(v/v) EtOAc in hexane) was crystallized from Et₂ O. The solid was driedin vacuo at 65° C.: (m.p. 125°-30° C.).

The compound was a single spot by TLC. The NMR spectrum was consistentwith the title structure and cnfirmed the presence of Et₂ O. Thecompound was greater than 95.7% pure by HPLC. The mass spectrum showed amolecular ion at m/e=409).

Anal. Calc'd for C₂₆ H₂₃ N₃ O₂.0.9C₄ H₁₀ O: C, 74.66; H, 6.77; N, 8.83.Found: C, 74.61; H, 6.80; N, 9.10.

EXAMPLE 511,3-Dihydro-3(RS)-(1-hydroxy-1-phenyl)methyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 47 was carried out using benzaldehyde (0.53 g,5 mmole) in place of indole-3-carboxaldehyde. The chromatographedproduct was crystallized from ether and dried in vacuo at 70°: (mp192°-193°).

The compound showed a single component by TLC (R_(f) =0.53, silica gelplate eluted with 1:1 (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure and showed the presence of 0.1mole of ether. The compound was 99.9% pure by HPLC. The mass spectrumshowed a molecular ion at m/e=338.

Analysis Calc'd for C₂₃ H₂₀ N₂ O₂.0.1C₄ H₁₀ O: C, 77.24; H, 5.82; N,7.70: Found: C, 77.11; H, 5.83; N, 7.93.

EXAMPLE 521,3-Dihydro-3(RS)-[1-hydroxy-1-(2-thienyl)]methyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 47 was carried out using2-thiophene-carboxaldehyde (0.56 g, 5 mmole) in place ofindole-3-carboxaldehyde. The chromatographed and evaporated product wascrystallized from ether and dried in vacuo at 70°: (mp 184°-185°).

The compound showed a single component by TLC (R_(f) =0.54, silica gelplate eluted with 1:1 (v/v) ether/methylene chloride). The NMR spectrumwas consistent with the title structure. The compound was 99.8% pure byHPLC.

Analysis Calc'd for C₂₁ H₁₈ N₂ O₂ S: C, 69.59; H, 5.01; N, 7.73; Found:C, 69.59; H, 5.10; N, 8.06.

EXAMPLE 531,3-Dihydro-3-(RS)-hydroxy-1-methyl-5-phenyl-3-(3'-thienoyl)-2H-1,4-benzodiazepin-2-one(A) and1,5-Dihydro-5-(RS)-hydroxy-1-methyl-5-phenyl-3-(3'-thienoyl)-2H-1,4-benzodiazepin-2-one(B)

The procedure of Example 47 was carried out using 0.75 g (5 mmole) of3-thienoyl chloride in place of indole-3-carboxaldehyde. In thisreaction, the THF employed was subsequently shown to contain significantquantities of organic peroxides. Workup and chromatography as in Example47 provided two products each of which was evaporated in vacuo andcrystallized from ether.

A: The first product obtained was A, which was dried in vacuo at 70°:(mp 193°-194°).

The compound showed a single component by TLC (R_(f) =0.57, silica gelplate eluted with 1:1 (v/v) methylene/chloride ether). The NMR spectrumwas consistent with the title structure. The compound was 99.4% pure byHPLC. The mass spectrum showed a molecular ion at m/e=376. The infrared

spectrum showed a strong absorption at 1675 cm⁻¹.

Analysis Calc'd for C₂₁ H₁₆ N₂ O₃ S: C, 67.00; H, 4.28; N, 7.44; Found:C, 67.04; H, 4.37; N, 7.49.

B: The second compound obtained was B, which was dried in vacuo at 70°:(mp 173°-175°).

The compound showed a single component by TLC (R_(f) =0.64, silica gelplate eluted with 1:1 methylene chloride/ether). The NMR spectrum wasconsistent with the title structure. The mass spectrum showed amolecular ion at m/e=376. The compound was 99.6% pure by HPLC. Theinfrared spectrum showed strong absorption at 1695 and 1720 cm⁻¹.

Analysis Calc'd for C₂₁ H₁₆ N₂ O₃ S: C, 67.00; H, 4.28; N, 7.44; Found:C, 66.91; H, 4.46; N, 7.32.

EXAMPLE 547-Chloro-1,3-dihydro-3(R)-[(2',3'-dihydro-2'-oxo-1'H-indol-3'-yl)methyl]-5-phenyl-2H-1,4-benzodiazepin-2-one

7-Chloro-1,3-dihydro-3(R)-indolylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one(200 mg, 0.5 mmol) was dissolved in DMSO (4.8 g, 10 mmol) followed bythe addition of concentrated HCl (5 mmol). The molar ratio of DMSO toHCl was 2:1. Additional reagents were added to drive the reaction tocompletion. The additions were:

    ______________________________________                                        0.71 ml DMSO        1.54 ml DMSO                                              0.4  ml HCl         0.75 ml HCl                                               ______________________________________                                    

When little starting material remained, the reaction was poured into anErlenmeyer flask with water (20 ml), and 5 g of NaHCO₃ was added. Water(100 ml) was added and the mixture was extracted with 4×50 ml ofn-butanol. The n-butanol solution was washed with water (3×100 ml). Then-butanol solution was evaporated and the residue was dissolved in etherand purified by preparative TLC.

The product was a pair of diasteriomers; the NMR spectrum was consistentwith the title compound.

HPLC indicated two components: 54% and 43%.

TLC in 95/5/0.5 CHCl₃ -MeOH-H₂ O R_(f) =0.3 (silica gel GF)

Mass Spec. gave a (M+1) at 416.

EXAMPLE 557-Chloro-1,3-dihydro-3(R)-[(3'-(2,4-dinitrophenyl)imidazol-5'-yl)-methyl]-5-phenyl-2H-1,4-benzodiazepin-2-one

Boc-DNP-D-Histidine (1.7 g, 4 mmol) and 2-amino-5-chlorobenzophenone(0.9 g, 4 mmol) were combined in 10 ml of THF and stirred until a clearorange solution was obtained. 4.3 mL of DCC (1M) in THF was added andthe reaction was stirred overnight. The reaction was filtered andevaporated. The residue was purified by flash chromatography on a silicagel 60 column with a 90:10 chloroform ether solvent system.

The resultant t-BOC protected compound was dissolved in 30 ml of ethylacetate. The solution was cooled to -25° C. HCl gas was added until thesolution was saturated. The temperature was allowed to rise to 0° C.When the reaction was complete by TLC, the ethyl acetate was evaporatedand the residue was dissolved in methanol. The pH of the solution wasadjusted with 10% aqueous sodium hydroxide to pH 9. After the reactionstirred overnight, the solvent was evaporated and the residue waschromatographed on a silica gel 60 column with chloroform, to give thetitle compound.

HPLC: 91%.

TLC: R_(f) =0.6 in 90/10/1 CHCl₃ -MeOH-aqueous ammonia (silica gel GF)

Mass Spec. molecular ion at 516.

NMR agreed with the title compound.

Elemental analysis for C₂₅ H₁₇ ClN₆ O₅.1.8H₂ O: Calcd: C, 54.65; H,3.82; N, 15.30. Observed: C, 54.38; H, 3.89; N, 15.31.

EXAMPLE 567-Chloro-1,3-dihydro-3(R)-(3'-imidazol-5'-yl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

This compound was obtained as a second Product from the reactionsequence of Example 55. This material, which had a positive Sanger testfor histidine, eluted from the silica column after the compound ofExample 55, HPLC: 87%

TLC: R_(f) -0.3 in 90/10/1 CHCl₃ -MeOH-aqueous ammonia (silica gel GF).

Mass Spec. molecular ion at 350.

NMR was consistent with the title compound.

Elemental Analysis for: C₁₉ H₁₅ ClN₄ O.93 H₂₈ O 0.2NH₃ : Calcd: C,61.29; H, 4.79; N, 16.33. Found: C, 61.68; H, 5.12; N, 16.61.

EXAMPLE 573(RS)-[3'-(5'-Bromoindolyl)methyl]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The synthesis was carried out as described for Example 55 starting withBoc-5-bromo-DL-tryptophan and 2-aminobenzophenone. The crude product waspurified by column chromatography (silica gel) using 90/10chloroform-ether as the elution solvent.

HPLC: 99%.

Elemental analysis calcd: N, 8.91; C, 61.15; H, 4.41. Found: N, 8.43; C,61.43; H, 4.20.

Mass Spec. molecular ion at 443.

NMR: The NMR was in agreement with the title compound.

EXAMPLE 585-o-Carboxyphenyl-1,3-dihydro-3(R)-(3+-indolyl)methyl-2H-1,4-benzodiazepin-2-one

2-Amino-2'-carboxybenzophenone (2.41 g, 10 mmol) was suspended in THF,CH₂ Cl₂, EtOAc and tryptophanyl chloride hydrochloride (2.59 g, 10 mmol)was added. The mixture was stirred at room temperature until reactionwas complete by TLC. A solid was collected by filtration, dried, anddissolved in 40 ml of methanol. The pH of the solution was adjusted to apH of 8-10 with 10% aqueous sodium hyroxide. After standing at roomtemperature for about 3 days, the solution was acidified to a pH ofabout 3. The solvent was evaporated and the residue was dissolved in95/5 CHCl₃ /CH₃ OH and flash chromatographed on a silica gel 60 columnwith a 95:5 and 90:10 chloroform-methanol solvent system to give thetitle compound.

HPLC: 96%. Elemental analysis calcd: C, 61.73; H, 3.97; N, 8.38 Found:C, 61.70; H, 4.09; N, 8.48.

Mass Spec. molecular ion observed at 409.

NMR: The spectrum agreed with the title compound.

EXAMPLE 591,3-Dihydro-3(RS)-[3'-(5'-fluoroindolyl)methyl]-5-o-fluorophenyl-2H-1,4-benzpdiazepin-2-one

5-Fluorotryptophyl chloride hydrochloride (1.38 g, 5 mmole), preparedfrom 5-fluoro-DL-tryptophan and PCl₁₅ in acetylchloride, was suspendedin 15 ml of THF. 2-Amino-2'-fluorobenzophenone 1.07 g (5.0 mmol) wasadded to the stirred mixture. After stirring overnight the solvent wasevaporated and the solid was dissolved in 50 ml of methanol. The pH ofthe solution was adjusted to 8-9 with 10% aqueous sodium hydroxide. Thesolution stood for 24 hours at room temperature. The solvent wasevaporated and the crude reaction product was purified by flashchromatography with 98:2 chloroform/methanol to give the title compound.

TLC: R_(f) =0.3 in 97:3 CHCl₃ /CH₃ OH (silica gel GF).

Elemental analysis calcd for C₂₄ H₁₇ F₂ N₃ O. 0.18CHCl₃ : C, 68.75; H,4.10; N, 9.94 Found: C, 68.78; H, 4.04; N, 9.85. NMR was in agreementwith the title compound.

EXAMPLE 601,3-Dihydro-3(RS)-[3'-(6'-fluoroindolyl)methyl]-5-o-fluorophenyl-2H-1,4-benzodiazepin-2-one

The compound was prepared according to the procedure of Example 59,using 6-fluorotryptophyl chloride hydochloride in place of the 5-fluorocompound.

The final product was obtained as a solid which crystallized in pureform from chloroform.

TLC R_(f) =0.4 in 97:3 CHCl₃ /CH₃ OH (silica gel GF)

Elemental analysis calcd: C, 70.62; H, 4.20; N, 10.26. Found: C, 70.62;H, 4.10; N, 10.25.

NMR was in agreement with the title compound.

EXAMPLE 612-N-[2(RS)3-bis-(Boc-amino)propanoyl]amino-2'-fluorobenzophenone

The procedure of Example 1 was carried out using2-amino-2'-fluorobenzophenone (430 mg, 2.0 mmole),2(R,S),3-bis-(Boc-amino)propionic acid (617 mg, 2.03 mmole), anddicyclohexylcarbodiimide (2.03 ml of a 1.0 M solution in methylenechloride) in 10 ml of methylene chloride. Filtration, concentration invacuo and flash chromatography (silica gel, 10% ethyl ether in methylenechloride) gave a foam, the PMR spectrum of which was consistent with thetitle compound.

EXAMPLE 622-N-[2(RS)-3-diphthalylaminopropanoyl]amino-2'-fluorobenzophenone

2-Amino-2'-fluorobenzophenone (2.10 g, 9.8 mmole) was reacted with2,3-diphthalylaminopropionyl chloride (5 g, 9.8 mmole) in 100 ml oftetrahydrofuran. After 2.5 hours the reaction mixture was rotoevaporaedto give 7 g of a yellow foam. The foam was heated for 30 minutes in 6Nhydrochloric acid (100 ml) and the resulting off-white solid collectedand dried. Recrystallization from ethyl acetate afforded the analyticalsample, m.p. 210.5°-211.5°. NMR (CD₃ OD): in agreement with titlecompound. Analysis Calc'd for C₃₂ H₂₀ FN₃ O₆ :

N, 7.48; C, 68.45; H, 3.59. Found: N, 7.46; C, 68.59; H, 3.63.

EXAMPLE 631,3-Dihydro-5-(2'-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-on

The procedure of Example 2 was carried out in which2-N-[2(RS)-((1,1-dimethylethoxy)carbonyl)amino-3-((1,1-dimethylethoxy)carbonyl)aminopropanoyl]-amino-2'-fluorobenzophenone(600 mg, 1.2 mmole) was reacted in succession with excess HCl gas inethyl acetate (15 ml) at 0° and then sodium hydroxide (0.1M solution) inaqueous methanol (10 ml). The pH of the reaction mixture wasapproximately 9.0. Work-up afforded the title compound as a solid, mp168°-169°; in 90% yield.

NMR (CDCl₃): Spectrum in agreement with title compound.

MS (14 ev.): 283 (M⁺) 253.

Analysis Calc'd for C₁₆ H₁₄ FN₃ O.0.05C₆ H₁₄ : N, 14.61; C, 68.07; H,5.15. Found: N, 14.87; C, 68.21; H, 5.33.

EXAMPLE 641,3-Dihydro-5-(2'-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one

2-N-[2(RS),3-diphthalylaminopropanoyl]amino-2'-fluorobenzophenone (1.07g, 1.90 mmole) was suspended in 55 ml of methanol and treated with 1 mlof 95% hydrazine. The reaction mixture was protected from moisture andstirred at room temperature. Within one hour, the reaction mixturebecame homogeneous. On further reaction, phthalhydrazide precipitatedfrom solution. After 14 hours, the reaction was filtered and thefiltrate concentrated. The residue was partitioned between methylenechloride and water; the organic phase was washed with water until it wasfree of hydrazine (Tollen's reagent negative), then dried andconcentrated to give 480 mg of an oil which crystallized on standing.Trituration of the resulting solid with ether gave the analyticalsample, m.p. 168°-169°, identical spectroscopically with the materialprepared in Example 63.

EXAMPLE 651,3-Dihydro-5-(2'-fluorophenyl)-3(R)-(4-amino)butyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 64 was followed whereby2-N-[2(R),6-diphthalylaminohexanoyl]amino-2'-fluorobenzophenone (5.4 g)was deprotected and cyclized with 10 ml of 95% hydrazine in 150 ml ofmethanol. Workup afforded 1.35 g of product which was purified viasilica gel chromatography (chloroform-methanol-ammonia, 80:30:4 v/v).

NMR (CDCl₁₃) in agreement with title compound.

Analysis Calc'd for C₁₉ H₂₀ FN₃ O.0.17CHCl₃ : N, 12.15; C, 66.60; H,5.88. Found: N, 12.32; C, 66.66; H, 6.05.

EXAMPLE 661,3-Dihydro-5-(2'-fluorophenyl)-3(RS)-(benzyloxycarbonyl)aminomethyl-2H-1,4-benzodiazepin-2-one

To a solution of 50 ml of methylene chloride containing 260 mg (0.91mmol) of1,3-dihydro-5-(2-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-oneand 224 mg (1.83 mmol) of 4-dimethylaminopyridine was added 0.51 ml(3.57 mmol) of benzylchloroformate. The resulting reaction mixture wasallowed to stand at room temperature overnight and then was diluted withmethylene chloride (200 ml). The reaction was then washed in successionwith saturated sodium bicarbonate solution and brine, then dried (MgSO₄)and concentrated. The residual oil was chromatographed on silica gel(chloroform-methanol-ammonia, 95:5:0.5 v/v elution) to afford 370 mg ofthe analytical product, m.p. 88° (soften), 90°-92° C.

TLC: Single component, R_(f) =0.35 (95:5:0.5, chloroform - methanol -ammonia).

NMR: Consistent with title structure.

Anal. calc'd for C₂₄ H₂₀ FN₃ O₃.1/4H₂ O: N, 9.96; C, 68.32; H, 4.89;Found: N, 9.86; C, 68.45; H, 5.15.

EXAMPLE 671,3-Dihydro-5-(2'-fluorophenyl)-3(RS)-(3-thiophene-carbonyl)aminomethyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-5-(2'-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one(140 mg, 0.49 mmole) and 3-thiophenecarbonyl chloride (88 mg, 0.60mmole) were dissolved in 10 ml of dry tetrahydrofuran at roomtemperature. To this solution was added 69 l of triethylamine. Afteraddition was complete, stirring was continued for 15 minutes more andthe reaction mixture was partitioned between ethylacetate (60 ml) andsodium bicarbonate solution (sat.). The organic phase was washed with10% sodium hydroxide solution (1×20 ml) and then with 10% hydrochloricacid solution. From this acidic solution were deposited off-whitecrystals, after overnight standing. The solid was washed with water anddried to give 140 mg of the analytical product, mp 237°-240° (Anadditional 70 mg of product was obtained as the free base afterconcentration of the organic extracts.) The analytical product wasgreater than 98% pure by HPLC.

MS (14 ev.): 393 (M-HCl), 266.

NMR (DMSO-d₆) in agreement with title compound.

Analysis Calc'd for C₂₁ H₁₇ ClFN₃ O₂ S: N, 9.77; C, 58.67; H, 3.98.Found: N, 9.89; C, 58.75; H, 4.17.

EXAMPLE 68 1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylaminomethyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-5-(2-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one(80 mg, 0.282 mmole) and indole-2-carbonyl chloride (53 mg, 0.30 mmol)were mixed in 5 ml of methylene chloride at room temperature. Thehomogeneous reaction mixture was protected from moisture and treatedwith 42 l (0.30 mmole) of triethylamine. Within five min., triethylaminehydrochloride precipitated. The reaction mixture was stirred at roomtemperatre overnight and then partitioned between methylene chloride andsaturated sodium bicarbonate solution. The resulting solid wascollected, washed with water and dried over P₂ O₅ at 70° C. In this way,39 mg of the analytical product was obtained, m.p.: 315°-317° (d).

NMR(DMSO-d₆): Consistent with the title structure.

MS: Molecular ion at m/e=426.

Anal. calc'd for C₂₅ H₁₉ FN₄ O₂.1.25 H₂ O: C, 66.88; H, 4.82; N, 12.48;Found: C, 66.76; H, 4.52. N, 12.25;

EXAMPLE 691,3-Dihydro-3'-(RS)-[3'-(RS)-(1,3-dihydro-5-(2'-fluorophenyl)-2H-1,4-benzodiazepin-2-one)-3-yl]methylaminomethyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-5-(2'-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one(60 mg, 0.21 mmole) was dissolved in 3 ml of isopropanol and treatedwith triethylamine (30 1, 0.22 mmole). The resulting solution was heatedto reflux for 18 hours, cooled and concentrated. The residual oil waschromatographed on silica gel (chloroform-methanol-ammonia, 90:10:1 v/v)to give 25 mg of the desired product as an off-white solid, mp 155°-158°(with gas evolution). MS (FAB): 550 (M+H), 549 (M⁺), 282 (base peak).

NMR (CDCl₃): in agreement with title compound.

Analysis Calc'd for C₃₂ H₂₅ F₂ N₅ O₂.0.35 CHCl₃ : N, 11.84; C, 65.70; H,4.32. Found: N, 11.68; C, 65.53; H, 4.46.

EXAMPLE 701,3-Dihydro-5-(2'-fluorophenyl)-3-(RS)-(6'-chloropyrazin-2yl)aminomethyl-2H-4-benzodiazepin-2-one

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one(72 mg, 0.25 mmol), 2,6-dichloropyrazine (45 mg, 0.30 mmol)and anhydrouspotassium carbonate (83 mg, 0.60 mmol) were combined at room temperaturewith 2 ml of dry dimethylformamide. The resulting suspension was stirredrapidly for 24 hours and 37 mg more of 2,6-dichlorpyrazine was added.After 72 hours total reaction time, the reaction mixture was poured intowater (10 ml) and extracted with ethyl acetate (3×20 ml). The combinedorganic extracts were washed with water and brine, dried (MgSO₄) andconcentrated to give 70 mg of crude product. The analytical sample wasobtained by preparative thick layer chromatography (chloroform -methanol - ammonia, 95:5:0.5 v/v one elution).

R_(f) =0.25, m.p. 140° (soften), 148°-152°.

NMR (CDCl₃) Consistent with the title structure.

MS (14 ev): 395 (M³⁰ ), 266, 254, 211.

Anal. calc'd for C₂₀ H₁₅ ClFN₅ O.1/4H₂ O: N, 17.49; C, 60.00; H, 3.90;Found: N, 16.59; C, 59.87; H, 3.90.

EXAMPLE 712-N-Methyl-N-[2(RS),3-diphthalylaminopropanoyl]amino-2'-fluorobenzophenone

Following the procedure of Example 4,2-N-[2(RS),3-diphthalylaminopropanoyl]amino-2'-fluorobenzophenone (677mg, 1.20 mmole) was converted to the title compound with sodium hydride(63 mg, 1.31 mmole) and methyliodide (81.5 μl, 1.31 mmole) in 5 ml ofN,N-dimethylformamide. Work-up afforded the crude product which waspurified by silica gel chromatography (ethyl acetate-hexane elution, 3:2v/v); the analytical sample was obtained as white prisms byrecrystallizing the chromatographed material from ethyl acetate, mp252°.

MS (14 ev.):575 (M³⁰ ), 453, 429, 309.

NMR (CDCl₃): in agreement with title compound.

Analysis Calc'd for C₃₃ H₂₂ FN₃ O₆. 0.15 C₄ H₈ O₂ : N, 7.13; C, 68.54;H, 3.94. Found: N, 7.12; C, 68.43; H, 4.26.

EXAMPLE 721,3-Dihydro-5-(2'-fluorophenyl)-3(RS)-aminomethyl-1-methyl-2H-1,4-benzodiazepin-2-one

Following the procedure of Example 64,2-N-methyl-N-[2(RS),3-diphthalylaminopropanoyl]amino-2'-fluorobenzophenone(220 mg, 0.38 mmole) was converted to the title compound with 95%hydrazine (1 ml) in 40 ml of methanol. The analytical material wasobtained via chromatography on silica gel (chloroform-methanol-ammonia,90:10:1 v/v). The PMR spectrum (CDCl₃) confirmed the structure of theproduct; N-methyl proton at 3.46 ppm.

EXAMPLE 733(RS)-1,3-Dihydro-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (75 mg,0.298 mmol), and indole-2-carbonyl chloride (58.8 mg, 0.327 mmol) werecombined in CH₂ Cl₂ (2 ml) and the pH adjusted to 9.0 with triethylamine(41 μl, 0.298 mmol). After stirring 10 min., the reaction waschromatographed on silica gel (180/10/1/1 of CH₂ Cl₂ /MeOH/H₂ O/HOAc).The combined product fractions were washed with dilute NaHCO₃ (aq) (1X),H₂ O (1X) and brine (1X), dried over MgSO₄, filtered and stripped togive the title compound as a white solid from ether: (m.p. 265°-268° ).

TLC: Silica GF (10% MeOH in CH₂ Cl₂), R_(f) =0.63, single homogeneouscomponent.

NMR: Consistent with title structure and verifies the presence of 0.2(C₂ H₅)₂ O.

HPLC: Greater than 99.2% pure.

M.S.: Mol. Ion=394 m/e (free base).

Anal. Calc'd for C₂₄ H₁₈ N₄ O₂.0.2 (C₂ H₅)₂ O:

C, 72.78; H, 4.93; N, 13.69; Found: C, 72.45; H, 4.60; N, 13.65.

EXAMPLE 741,3-Dihydro-3(RS)-[2-(3-indolyl)ethyl]amino-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-Chloro-1,3,-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (68 mg,0.25 mmol), 3-(2-aminoethyl)indole (40 mg, 0.25 mmol), and sodiumhydroxide (0.1 ml of 2.5N solution) were combined in methanol (4 ml) andstirred at room temperature for 18 hours. The mixture was evaporated invacuo, and the residue was dissolved in methylene chloride andchromatographed on silica gel (5% v/v MeOH in CH₂ Cl₂). The productfractions were evaporated in vacuo and the resulting solid crystallizedfrom ether and dried in vacuo at 60°: (m.p. 196°-197.5° (d)). TLC:Single spot (R_(f) =0.46, silica gel plate, 10% (v/v) MeOH in CH₂ Cl₂).

NMR: The spectrum was consistent with the title structure and verifiedthe presence of CH₂ Cl₂.

HPLC: Greater than 94% pure.

MS: A molecular ion at m/e=394.

Anal. calc'd. for C₂₅ H₂₂ N₄ O.0.13 CH₂ Cl₂ : C, 74.43; H, 5.53; N,13.82; Found: C, 74.62; H, 5.47; N, 13.62.

EXAMPLE 753(RS)-[3-(3-indolyl)propionylamino]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 77 was carried out using 3-(3-indolyl)propionicacid (0.076 g, 0.4 mmol) in place of BOC-L-tryptophan. The product waschromatographed on silica gel using a gradient of 1:1 Et₂ O/CH₂ Cl₂containing 0 to 2% CH₂ OH. The product was crystallized from acetone anddried in vacuo at 60°: (m.p. 176°-182° ).

TLC: Single spot (R_(f) 0.66, silica gel plate, 10% (v/v) MeOH in CH₂Cl₂).

NMR: The spectrum was consistent with the title structure.

HPLC: 99.7% pure.

MS: A molecular ion at m/e=422.

Anal. calc'd for C₂₆ H₂₂ N₄ O₂.0.5H₂ O:

C, 72.37; H, 5.37; N, 12.99; Found: C, 72.31; H, 5.57; N, 12.98.

EXAMPLE 763(RS)-(3-indoleacetylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (75 mg,0.298 mmol) and indole-3-acetyl chloride (57.8 mg, 0.298 mmol) werecombined in CH₂ Cl₂ (2 ml) and the pH adjusted to 9.0 with triethylamine(TEA) 41 μml, 0.298 mmol). After stirring 15 min., a second portion ofindole-3-acetyl chloride (44 mg, 0.175 mmol) and TEA (30μ, 0.215 mmol)were added and the reaction stirred an additional 15 min. The completedreaction was diluted with CH₂ Cl₂, washed with H₂ O (lX) and brine (1X),dried over MgSO₄, filtered and stripped to dryness in vacuo. The residuewas chromatographed on silica gel (5% MeOH in CH₂ Cl₂) to give the titlecompound as a pinkish solid from Et₂ O:(m.p. 264°-265° ).

TLC: Silcia GF (10% MeOH in CH₂ Cl₂), R_(f) =0.44, single homogeneouscomponent.

NMR: Consistent with title structure.

HPLC: Greater than 93.1% pure.

M.S.: molecular ion at m/e=408.

Anal. calc'd for C₂₅ H₂₀ N₄ O₂ C, 73.51; H, 4.94; N, 13.72; Found: C,73.54; H, 4.94; N, 13.32.

EXAMPLE 773(RS)-(Boc-L-tryptophanyl)amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (0.1 g, 0.4mmol), BOC-L-tryptophan (0.12 g, 0.4 mmol), and DCC (0.4 ml of a 1 Msolution in CH₂ Cl₂, 0.4 mmol) were combined in 2 ml of THF to whichwere added 2 ml of DMF and 2 ml of CH₂ Cl₂. The mixture was treated withtriethylamine (0.11 ml), stoppered, and stirred at room temperature forfour days. The mixture was treated with citric acid solution (10%, 3 ml)and CH₂ Cl₂ (5 ml), shaken and separated. The aqueous phase wasextracted with CH₂ Cl₂ (2×5 ml). The combined organic layers were washedwith citric acid (10%, 2×5 ml), sodium bicarbonate (10%, 2×5 ml), and H₂O (10 ml), dried over sodium sulfate, filtered, and evaporated todryness in vacuo. The residue was chromatographed on silica gel (1:1(v/v) Et₂ OCH₂ Cl₂) and the combined product fractions evaporated todryness in vacuo. The residue was triturated with petroleum ether andthe solid dried in vacuo at 70° : (m.p. 173°-177° (↑)).

TLC: Single spot (R_(f) =0.56, silica gel plate, 10% (v/v) CH₃ OH in CH₂Cl₂).

NMR: The spectrum was consistent with the title structure and verifiedthe presence of two diastereomers.

HPLC: Greater than 99.7% pure (36% and 63.7%).

MS (FAB): a molecular ion at m/e=537.

Anal. calc'd for C₃₁ H₃₁ N₅ O₄ C, 69.25; H, 5.81; N, 13.03;

Found: C, 69.48; H, 6.18; N, 12.96.

EXAMPLE 781-Carboxymethyl-1,3-dihydro-3(RS)-(2-indolearbonyl-amino)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using1,3-dihydro-3(RS)-(2-indolecarbonylamino)-5-Phenyl-2H-1,4-benzodiazepin-2-one(0.87 g, 2.2 mmol) in place of1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-oneand ethyl bromoacetate (0.38 g, 2.25 mmole) in place of methyl iodide.The chromatographed product (7% ether in CH₂ Cl₂) (0.073 g, 0.15 mmol)and sodium hydroxide (0.2 ml, 1N, 0.2 mmol) were stirred together in CH₃OH (1 ml) at room temperature for 18 hours. The mixture was concentratedin vacuo, diluted to 3 ml with H₂, made acidic with 1N HCl, andextracted with CH₂ Cl₂ (3×5 ml). The combined organic layers weretreated with methanol (1 ml) to dissolve precipitated solid, dried overNa filtered, and evaporated to dryness in vacuo. The residue wascrystallized from ether (4 ml) and the solid dried in vacuo at 80°:(m.p. 275°-278° (d) (↑)).

TLC: A single spot (R_(f) =0.21, silica gel plate, 180:10:1:1 (v/v/v/v)CH₂ Cl₂ :MeOH:HOAc: H₂ O).

NMR: Spectrum was consistent with the title structure and verified withpresence of Et₂ and CH₂ Cl₂.

HPLC: Greater than 98.5% pure.

MS: A molecular ion at m/e=452.

Anal. calc'd for C₂₆ H₂₀ N₄ O₄. 0.3 CH₂ Cl₂.0.3 C₄ H₁₀ O:

C, 66.03; H, 4.76; N, 11.20; Found: C, 65.93; H, 4.56; N, 11.22.

EXAMPLE 791,3-Dihydro-3(RS)-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(A) and1,3-dihydro-1-methyl-3(RS)-[2-(1-methylindole)carbonylamino]-5-phenyl-2H-1,4-benzodiazepin-2-one(B)

The procedure of Example 4 was carried out using1,3-dihydro-3(RS)-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one(0.87 g, 2.2 mmol) in place of1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3.-indolyl)methyl-2H-1,4-benzodiazepin-2-one.Chromatography using 7(v/v) diethyl ether in CH₂ Cl₂ and evaporation ofthe product fractions in vacuo gave A and B which were each crystallizedfrom ether and dried in vacuo at 80°.

Compound A: (m.p. 268°-270° (d))

TLC: A single spot (R_(f) =0.43, silica gel plate, 10% (v/v) Et₂ O n CH₂CH₂ Cl₂).

NMR: Spectrum was consistent with the title structure and verified thepresence of Et₂ O and CH₂ Cl₂.

HPLC: 99% pure.

MS: A molecular ion at m/e=408.

Anal. calc'd for C₂₅ H₂₀ N .0.15 CH₂ Cl₂. 0.1 C₄ H₁₀ O:

C, 71.60; H, 5.01; N, 13.07; Found: C, 71.79; H, 5.01; N, 13.01.

Compound B: (m.p. 202.5°-203° ).

TLC: A single spot (R_(f) =0.67, silica gel plate, 10% (v/v) Et₂ O inCH₂ Cl₂).

NMR: Spectrum was consistent with the title structure.

HPLC: Greater than 98.2% pure.

MS: A molecular ion at m/e=422.

Anal. calc'd for C₂₆ H₂₂ N₄ O₂ :

C, 73.91; H, 5.25; N, 13.26; Found: C, 74.05; H, 5.20; N, 13.51.

EXAMPLE 801,3-Dihydro-1-methyl-3(RS)-(4-chlorophenylcarbonyl)-amino-5-(2-fluoroohenyl)-2H-1,4-benzodiazeoin-2-one

To a suspension of sodium hydride (50%) (84 mg, 1.82 mmole) in 4 ml ofdry dimethylformamide at 0° C. was added, under nitrogen,1,3-dihydro-3(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(648 mg, 1.59 mmole). The resulting reaction miture became homogeneousover a one-hour period, was stirred one hour more at 0° C. and thentreated with iodomethane (108 μl, 1.74 mmole). The reaction mixture waswarmed to room temperature and after one hour was quenched with brine.The aqueous mixture was extracted with ethyl acetate and the combinedorganic extracts were washed with brine. Rotoevaporation of the driedextracts (MgSO₄) gave a semi-solid which was chromatographed on silicagel (chloroform-methanol-ammonia 95:5:0.5 v/v elution) to give 130 mg ofrecovered starting material and 360 mg of the analytical sample R_(f)=0.78, m.p. 171.5°-172° C.

NMR (CDCl₃): consistent with the title structure MS (14 ev): 421 (M⁺)282, 266, 255,241.

Analysis calc'd for C₂₃ H₁₇ ClFN₃ O₂ : Calc'd: N, 9.96; C, 65.48; H,4.06. Found: N, 10.08; C, 65.79; H, 4.08.

EXAMPLE 811,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonyl-amino)-1-methyl-2H-1,4-benzodiazepin-2-one(A) and1,3-Dihydro-5-(2-fluorophenyl)-1-methyl-3(RS)-[2'-(1-methylindole)carbonylamino]-2H-1,4-benzodiazepin-2-one(B)

The procedure of Example 4 was carried out using1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one(0.91 g, 2.2 mmole) in place of1,3-dihydro-5-(2-fluoro-phenyl)-3(R)(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one.Chromatography using 10% (v/v) diethyl ether in CH₂ Cl₂ and evaporationof the product fractions in vacuo gave A and B which were eachcrystallized from Et₂ O/CH₂ Cl₂ (2/1, v/v) and dried in vacuo at 40° C.

Compound A: (m.p. 282°-283.5° ). .

TLC: A single spot (R_(f) =0.53, silica gel plate, 10% (v/v) Et₂ O inCH₂ Cl₂).

NMR: The spectrum was consistent with the title structure and verifiedthe presence of ether (1/2mole) and CH₂ Cl₂ (3/4 mole).

HPLC: Greater than 97% pure.

MS: A molecular ion at m/e=426.

Anal. calc'd for C₂₅ H₁₉ FN₄ O₂.0.5. C₄ H₀.0.0.75 CH₂ Cl₂ :

C, 63.22; H, 4.88; N, 10.63; Found: C, 63.41; H, 4.66; N, 10.59.

Compound B: (m.P. 178°-181° )

TLC: A single spot (R_(f) =0.76, silica gel plate, 10% (v/v) Et₂ O inCH₂ Cl₂).

NMR: The spectrum was consistent with the title structure.

HPLC: Greater than 89% pure.

M.S.: A molecular ion at m/e=440.

Anal. calc'd for C₂₆ H₂₁ FN₂ O₂ 0.75 H₂ O:

C, 68.78; H, 4.99; N, 12.34; Found: C, 68.76; H, 4.73; N, 12.38.

EXAMPLE 823(RS)-(2(S)-tert-Butoxycarbonylamino-3-phenylpropanoyl-amino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (1.3 g,5.17 mmole), Boc-L-Phenylalanine (1.37 g, 5.17 mmole), HBT (0.70 g, 5.17mmole), and EDC (0.99 g, 5.17 mmole) were combined in DMF (30 ml) andstirred at room temperature. The pH of the mixture was adjusted to 9.5with triethylamine. After 1/2 hour, the DMF was removed in vacuo and theresidue treated with 10% citric acid (10 ml), neutralized with Na_(CO) ₃and extracted with CH₂ Cl₂ (3×15 ml). The combined organic layers werewashed with water, dried over Na₂ CO₃ filtered, and evaporated todryness in vacuo. The residue was chromatographed on silica gel(90/3/0.3/0.3 CH₂ Cl₂ /MeOH/H₂ /HOAc) and the combined product fractionsevaporated to dryness in vacuo. The residue was dissolved in CH₂ Cl₂ (10ml), washed with saturated Na₂ CO₃ solution (2 ml), dried over Na₂ SO₄,filtered and evaporated to dryness. The residue was treated with Et₂ Oand evaporated five times to give the title compound as a mixture ofdiastereomers (m.p. 143°-153° C.).

TLC: silica gel (90/10/1/1 CH₂ Cl₂ /MeOH/MoAc/H₂), R_(f) =0.58

NMR: consistent with structure HPLC: 97.5% pure (two diastereomers, 1:1)

M.S.: A molecular ion at m/e=498.

Anal. Calc'd for C₂₂₉ H₃₀ N₄ O₄ : Calcd: C, 69.86; H, 6.07; N, 11.24.Found: C, 69.58; H, 6.12; N, 11.22.

EXAMPLE 833(RS)-(2(S)-tert-Butoxycarbonylamino-3-phenylpropanoyl-amino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodi-azepin-2-one

3(RS)-(2(S)-tert-Butoxycarbonylamino-3-phenyl-Propanoylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one(2.5 gm, 5.01 mmol) was dissolved in DMF (20 ml) cooled to 0° C.,treated with a 50% oil dispersion of sodium hydride (241 mg, 5.01 mmol)and stirred 30 minutes. The resulting orange solution was treated withmethyl iodide (711 mg, 5.01 mmol) and stirred 1 hour at 25° C. The DMFwas removed in vacuo, and the resulting residue treated with dilute Na₂CO₃ (aqueous) and extracted with EtOAc (3x). The organic extracts werecombined, washed with H₂ O (1x), dried over MgSO₄, filtered andevaporated to dryness in vacuo to give a yellow oil (3.57 gm). Flashchromatography on silica gel (15% EtOAc in CH₂ Cl₂) gave the titlecompound as a white foam (1.8 gm) from ether: (m.p. 117°-20° C.)(soften)).

TLC: Silica GF (180/10/1/1 of CH₂ Cl₂ /MeOH/H20/HoAc R_(f) =0.48, clean,homogeneous component

NMR: Consistent with structure

HPLC: 98.5% pure (as a 1/1 mixture of diastereomers)

M.S.: Molecular ion at m/e=512.

Anal. calc'd for C₃₀ H₃₂ N₄ O₄ :

C, 70.29; H, 6.29; N, 10.93; Found: C, 69.99; H, 6.32; N, 10.81.

EXAMPLE 84 (R andS)-(2(S)-Amino-3-phenylpropanoylamino)-1,3-dihydro-1-methYl-5-phenyl-2H-1,4-benzodiazepin-2-one

3(RS)-(2(S)-tert-Butoxycarbonylamino-3-phenyl-propanoylamino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(1.8 gm, 3.51 mmol) was dissolved in EtOAc (25 ml), cooled to 0° C., andthe solution saturated with HCl (g) over a 10 minute period. Afterstirring an additional 10 minutes the solvent was removed in vacuo. Thesolid residue was dissolved in H₂₀, basified with saturated Na₂ CO₃(aq.) and extracted with EtOAc (3x). The organic layers were combined,washed with brine, dried over Na₂ SO₄, filtered and stripped to drynessin vacuo to give a grey foam (1.46 gm). Flash chromatography on silicagel (90/10/1/1 of CH₂ Cl₂ / MeOH/H20/HOAc) separated the 1/1 pair ofdiastereo-mers into a clean upper (R_(fl=) 0.36) and clean lower (Rf=024) component. Each component was evaporated to dryness in vacuo,dissolved in CH₂ Cl₂, washed with saturated Na₂ CO₂ (aq.) (lx), brine(1x), dried over Na₂ SO₄ and filtered. The individual filtrates wereconcentrated to dryness to give the separated diastereomers as whitefoams (upper component, 605 mg; lower component, 570 mg).

A: Upper Component(3(S)isomer): (m.p. 92°-108° C. (shrink and soften))TLC: Silica gel (90/10/1/1 of CH₂ Cl₂ /l MeOH/H₂ /HoAc) R_(f) =0.36,single, homogeneous component

NMR: Consistent with structure.

HPLC: Greater than 98.8% single component (100% diastereomericallypure).

M.S.: Molecular ion at m/e=412

Anal. calc'd for C₃₅ H₂₄ N₄ O₂ :

C, 72.79; H, 5.87; N, 13.58; Found: C, 72.79; H, 5.96; N, 13.31.

(shrink and soften))

B: Lower Component (3)(R)isomer): (m.p. 97°-108° C.

TLC: silica gel (90/10/1/1 of CH₂ Cl₂ /MeOH/H₂ O/HoAc)

R_(f) =0.24, single, homogeneous component

NMR: Consistent with structure.

HPLC: Greater than 99.2% single component (containing less than 0.8% ofupper component)

M.S.: Molecular ion at m/e=412

Anal. calc'd for C₂₅ H₂₄ N₄ O₂ :

C, 72.79; H, 5.87; N, 13.58; Found: C, 72.44; H, 5.85; N, 13.48.

EXAMPLE 85 3(R)- and3(S)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

A:3(S)-(2(S)-amino-3-phenylpropanoylamino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(Example 84, upper component), (1.15 g, 2.79 mmole) was combined withphenylisothiocyanate (395 mg, 2.93 mmole) in CH₂ Cl₂ (20 ml) and themixture concentrated on a steam bath. The resulting oil was twicediluted with CH₂ Cl₂ (20 ml) and both times re-concentrated on the steambath. The oil was evaporated in vacuo to a foam which was treated withTFA (15 ml) and warmed for 18 minutes in an oil bath thermostatted at52°. The TFA was removed in vacuo. The residue was treated twice withCH₂ Cl₂ and with Et₂ O, evaporated in vacuo after each treatment, andthe resulting oil chromatographed on silica gel (90/10/1/1 of CH₂ Cl₂/MeOH/H₂ /HoAc) The product fractions were evaporated in vacuo, and theresidue was dissolved in CH₂ Cl₂, washed with a small volume of 5% NaOH,dried over Na₂ SO₄, filtered, and evaporated to give the levorotatory(3(S)) isomer of the title structure.

TLC: Silica gel (90/10/1/1 CH₂ Cl₂ /MeOH/H₂ /HoAc) R_(f) =0.31 NMR:Consistent with structure, verifies presence of

0.15 mole of EtOAc

HPLC: Greater than 97.6% pure

M.S.: Molecular ion at m/e=265 [α]_(D) ²⁵ =-236° (0.0033 g/ml, C₄ H₁₀ O:

Anal. calc'd for C₁₆ H₁₅ N₃ O.0.15 C₄ H₁₀ O:

C, 71.43; H, 6.07; N, 15.06;

Found: C, 71.44; H, 5.95; N, 15.11.

B:3(R)-(2(S)-amino-3-phenylpropanoylamino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(Example 84, lower component) was converted by the same procedure to thedextrorotatory (3(R) enantiomer of the title compound.

TLC: Silica gel (90/10/1/1

CH₂ Cl₂ /MeOH/H₂ O/HoAC)

R_(f) =0.31

NMR: Consistent with structure, verifies presence of 0.15 mole of EtOAc

HPLC: Greater than 96.7% pure

M.S.: Molecular ion at m/e=265 [α_(D) ²⁵ =+227° (0.0033 g/ml, CH₂ Cl₂)

Anal. calc'd for C₁₆ H₁₅ N₃ O.15 H₂ C₄ H₁₀ O:

C, 71.43; H, 6.07; N, 15.06; Found: C, 71.14; H, 5.99; N, 14.90.

EXAMPLE 86 (R) and3(S)-Amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 82 was carried out using3-(RS)-amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-onein place of3-(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one. Theproduct was methylated using the procedure of Example 3 and theresulting methyl derivative was deprotected and separated using theprocedure of Example 84. The separated isomers were each treated withPhenyl isothiocyanate followed by TFA according to the method of Example85 giving the 3(R) and 3(S) isomers of the title compound.

3(S) isomer:

H TLC Silica gel (90/10/1/1 CH₂ Cl₂ /MeOH/H₂ O/HoAc),

R_(f) =0.37

NMR: Consistent with structure

HPLC: 95% pure

M.S.: Molecular ion at m/e=283 [α_(D) ²⁵ =-b 8.3° (0.0025 g/ml, CH₂/Cl₂)

3(R) isomer:

TLC: Silica gel (90/10/1/1 CH₂ Cl₂ /MeOH/H₂ O/HoAc),

R_(f) =0.37

NMR: Consistent with structure

M.S.: Molecular ion at m/e=283 [α]_(D) ²⁵ +71.4° (0.0028 g/ml, CH₂ Cl₂)

EXAMPLE 873(S)-(-)-1,3-Dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

3(S)-(-)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(595 mg, 2.24 mmole) was dissolved in CH₂ Cl₂ (15 ml) and treated with2-indolecarbonyl chloride (403 mg, 2.24 mmole) followed by triethylamine(227 mg, 2.24 mmole). The mixture was stirred at room temperature for 30minutes and concentrated in vacuo. The residue was chromatographed onsilica gel (5% Et₂ O/CH₂ Cl₂) and the combined product fractionsevaporated to dryness in vacuo. Three times, Et₂ O (15 ml) was added andevaporated in vacuo to give the title compound: (m.p. 168°-185°).

TLC: Silica gel (6% Et₂ O/CH₂ Cl₂), R_(f) =0.23

NMR: Consistent with structure

HPLC: Greater than 99% pure

M.S.: Molecular ion at m/e=408

[α]_(D) ²⁵ =-103° (0.0078 g/ml, CH₂ Cl₂)

Anal. calc'd for C₂₅ H₂₀ N₄ O₂ : C, 73.51; H, 4.94; N, 13.72; Found: C,73.38; H, 4.80; N, 13.66.

EXAMPLE 883(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-indole-carbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 87 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-onein place of3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.The title compound was obtained as a foam: (m.p. 162°-187°).

TLC: Silica gel (10% Et₂ O/CH₂ Cl₂) R_(f) =0.30

NMR: Consistent with structure, verifies presence of 0.2 Et₂ O

HPLC: Greater than 99.6% pure

M.S.: Molecular ion at m/e=426

[α]_(D) ²⁵ =+5.57° (0.0031 g/ml, CH₂ Cl₂)

Anal. calc'd for C₂₅ H₁₉ FN₄ O₂.0.2C₄ H₁₀ O: C, 70.22; H, 4.80; N,12.70; Found: C, 70.13; H, 4.75; N, 12.61.

EXAMPLE 893(R)-(-)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-indole-carbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 88 was carried out using3(R)-(+)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-onein place of its 3(S)-(-) isomer. The title compound was obtained as afoam; (m.p. 162°-187°)

TLC: Silica gel (10% Et₂ O/CH₂ Cl₂) R_(f) =0.30

NMR: Consistent with structure, verifies presence of 0.1 Et₂ O

HPLC: Greater than 99.6% pure

M.S.: Molecular ion at m/e=426

[α]_(D) ²⁵ =-5.65° (0.0023 g/ml, CH₂ Cl₂)

Anal. calc'd for C₂₅ H₁₉ FN₄ O₂.0.1C₄ H₁₀ O: C, 70.31; H, 4.65; N,12.92; Found: C, 70.16; H, 4.64; N, 12.86.

EXAMPLE 903(R)-(-)-1,3-Dihydro-3-(4-chlorobenzoylamino)-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

3(R)-(+)-3-Amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(350 mg, 1.24 mmole) was dissolved in CH₂ Cl₂ (4 ml) and treated with4-chlorobenzoyl chloride (217 mg, 1.24 mmole) followed by triethylamine(125 mg, 1.24 mmole). The mixture was stirred at room temperature for 30minutes and concentrated in vacuo. The residue was chromatographed onsilica gel (4% Et₂ O/CH₂ Cl₂) and the combined product fractionsevaporated to dryness in vacuo. Ether was added and removed in vacuothree times, giving the title compound as a foam; (m.P. 113°-128°).

TLC: Silica gel (10% Et₂ O/CH₂ Cl₂) R_(f) =0.43

NMR: Consistent with structure

HPLC: Greater than 99.6% pure

M.S.: Molecular ion at m/e=421

[α]_(D) ²⁵ =-12.8° (0.0031 g/ml, CH₂ Cl₂)

Anal. calc'd for C₂₃ H₁₇ ClFN₃ O₂ : C, 65.48; H, 4.06; N, 9.96; Found:C, 65.48; H, 4.17; N, 9.93.

EXAMPLE 913(S)-(+)-1,3-Dihydro-3-(4-chlorobenzoylamino)-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 90 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-onein place of its 3(R)-(+)-isomer. The title compound was obtained as afoam; (m.p. 113°-128°).

TLC: Silica gel (10% Et₂ O/CH₂ Cl₂) R_(f) =0.43

NMR: Consistent with structure.

HPLC: Greater than 99.6% pure M.S. Molecular ion at m/e=421

[α]_(D) ²⁵ =+13.2° (0.0032 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ ClFN₃ O₂ C, 65.48; H, 4.06; N, 9.96; Found: C,65.43; H, 4.09; N, 9.81.

EXAMPLE 923(S)-(-)-1,3-Dihydro-3-(4-bromobenzoylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

3(S)-(-)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(35 mg, 0.132 mmole) was dissolved in CH₂ Cl₂ (1 ml) and treated with4-bromobenzoylchloride (29 mg, 0.132 mmole) followed by triethylamine(13.3 mg, 10.132 mmole). The mixture was stirred at room temperature for30 minutes and concentrated in vacuo. The residue was chromatographed onsilica gel (3% Et₂ O/CH₂ Cl₂) and the combined product fractionsevaporated to dryness in vacuo. Ether was added and removed in vacuothree times, giving the title compound as a foam; (m.p. 120°-133°).

TLC: Silica gel (7% Et₂ O/CH₂ Cl₂), R_(f) =0.36

NMR: Consistent with structure

HPLC: Greater than 99.1% pure

M.S.: Molecular ion at m/e 447

[α]_(D) ²⁵ =-72.4° (0.0027 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₈ BrN₃ O₂ : C, 61.62; H, 4.05; N, 9.37; Found: C,61.94; H, 4.07; N, 9.20.

EXAMPLE 933(R)-(+)-1,3-Dihydro-3-(4-bromobenzoylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 92 was carried out using3(R)-(+)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one in place of its 3(S)-(-) isomer. The titlecompound was obtained as a foam; (m.p. 120°-133°)

TLC: Silica gel (7% Et₂ O/CH₂ Cl₂); R_(f) 0.36

NMR: Consistent with structure

HPLC: Greater than 99.2% pure

M.S.: Molecular ion at m/e447

[α]_(D) ²⁵ =+75.1° (0.0022 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₈ BrN₃ O₂ : C, 61.62; H, 4.05; N, 9.37; Found: C,62.00; H, 4.12; N, 9.27.

EXAMPLE 943(R)-(+)-1,3-Dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 87 was carried out using3(R)-(+)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-onein place of its 3(S)-(-) isomer. The title compound was obtained as afoam; (m.p. 168°-185°).

TLC: Silica gel (6% EtO/CH₂ Cl₂); R_(f) =0.23

NMR: Consistent with structure

HPLC: Greater than 99.2% pure

M.S.: Molecular ion at m/e=408

[α]_(D) ²⁵ =+100° (0.0052 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₅ H₂₀ N₄ O₂ : C, 73.51; H, 4.94; N, 13.72; Found: C,73.16; H, 4.88; N, 13.53.

Effective daily dosages of compounds such as those of Examples 79, 83,84, 87 and 88 can range to as low as 0.01 mg/kg.

EXAMPLE 95Z-1,3-Dihydro-1-methyl-5-phenyl-3-(3-thienylmethylene)-2H-1,4-benzodiazepin-2-oneandE-1,3-Dihydro-1-methyl-5-phenyl-3-(3-thienylmethylene)-2H-1,4-benzodiazepin-2-one

To a cooled (-60° C.) solution of diisopropylamine (0.84 ml, 6.0 mmol)in THF (10.2 ml) was added 1.5M butyllithium in hexane (4.0 ml, 6.0mmol). The solution was stirred 10 min. at -60° C. and then warmed to25° C. The light yellow solution was recooled to -60° C. and treatedwith solid 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (75mg, 3.0 mmol) portionwise (5×15 mg). The reaction was permitted to warmto 0° C. and then recooled to -60° C. A solution ofthiophene-3-carboxaldehyde (336 mg, 3.0 mmol) in THF (6 ml) was added tothe deep red anion solution, the cooling bath was removed, and thereaction allowed to warm to 25° C. The reaction was quenched with brineand extracted with ether (3X). The combined extracts were washed with H₂O (1X), dried over MgSO₄, filtered, and stripped to dryness in vacuo.The crude red oil was chromatographed on silica gel (10% Et₂ O in CH₂Cl₂) to give the intermediate alcohol as a buff-colored solid: 210 mg,m.p. 188°-9° C.

TLC: silica GF (10% Et₂ O in CH₂ Cl₂ single homogeneous component. Aportion of this product (171 mg, 0.472 mmol) was refluxed in a mixtureof trifluoroacetic acid (3 ml) and trifluoroacetic anhydride (1 ml) for12 hrs. The solvent was removed in vacuo and the residue was treatedwith H₂ O, basified with 10% NaOH (aq) and extracted with ether (3X).The combined extracts were washed with H₂ O (1X), dried over MgSO₄,filtered and stripped to dryness in vacuo to give a crude oil.Chromatography on silica gel (2% Et₂ O in CH₂ Cl₂) provided the titlecompounds which were obtained as light yellow solids from ether.

Z-isomer: (m.p. 196°-197° C.).

TLC: Silica GF (4% Et₂ O in CH₂ Cl₂), R_(f) =0.37, single homogeneouscomponent.

PMR: Consistent with the title structure.

HPLC: Greater than 99.8% pure.

M.S.: Mol. ion=344 m/e.

Anal. calc'd for C₂₁ H₁₆ N₂ OS: C, 73.23; H, 4.68; N, 8.13; Found: C,73.37; H, 4.78; N, 7.79.

E-isomer: (m.p. 194°-196° C.).

TLC: Silica GF (4% Et₂ O in CH₂ Cl₂), R_(f) =0.28 single homogeneouscomponent.

PMR: Consistent with the title structure.

HPLC: Greater than 99.9% pure.

M.S.: Mol. ion=344 m/e.

Anal. calc'd for C₂₁ H₁₆ N₂ OS: C, 73.23; H, 4.68; N, 8.13; Found: C,73.12; H, 4.83; N, 7.73.

EXAMPLE 963(RS)-(BOC-D-tryptophanyl)amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 77 was carried out using BOC-D-tryptophan inplace of BOC-L-tryptophan. The chromatographed product was crystallizdfrom Et₂ O and dried in vacuo at 80°: (m.P. 171°-174° (c)).

TLC: A single spot (R_(f) =0.56, silica gel plate, 10% (v/v) CH₃ OH inCH₂ Cl₂).

NMR: The spectrum was consistent with the title structure and verifiedthe presence of two diastereomers.

HPLC: Greater than 98.4% pure (68.9% and 29.5%).

Anal. calc'd for C₃₁ H₃₁ N₅ O₄ : C, 69.25; H, 5.81; N, 13.03; Found: C,69.24; H, 6.03; N, 13.04.

EXAMPLE 973(RS)-[4-(3-Indole)butyrylamino]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 77 was carried out using 4-(3-indolyl)butyricacid (0.082 g, 0.4 mmol) in place of BOC-L-tyrptophan. The product waschromatographed as in Example 75, crystallized from a mixture of acetone(1 ml) and ether (3 ml), and dried in vacuo at 80°: (m.p., 258°-259°).

NMR: The spectrum was consistent with the title structure.

HPLC: 98.9% pure.

MS: A molecular ion at m/e=436.

Anal. calc'd for C₂₇ H₂₄ N₄ O₂ : C, 74.29; H, 5.54; N, 12.84; Found: C,74.39; H, 5.65; N, 12.93.

EXAMPLE 981,3-Dihydro-3(RS)-(benzyloxycarbonyl)aminomethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine

To a magnetically stirred solution of1,3-dihydro-3(RS)-benzyloxycarbonyl)aminomethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-thione(1.85 g, 4.3 mmol) in 150 ml of ethanol were added, at room temperature,three portions of freshly prepared Raney nickel (slurried in ethanol,approximately 4°-5 g). The resulting reaction mixture was stirredvigorously overnight and treated with an additional equal portion ofRaney nickel. After 50 hours of total reaction time, the suspension wasfiltered carefully; the residual Raney nickel was washed copiously withethanol. Concentration of the filtrate under reduced pressure gave 880mg of product essentially homogeneous by TLC (ethyl acetate-hexane 1:1v/v). The analytical sample was obtained via silica gel chromatography(chloroform-methanol 96:4) as a foam.

TLC, HPLC greater than 97% pure.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 403 (M⁺), 295, 253, 239, 219.

Anal. calc'd for C₂₄ H₂₂ FN₃ O₂. 0.03 CHCl₃ : N, 10.32; C, 70.90, H,5.45; Found: N, 10.16; C, 70.89; H, 5.60.

EXAMPLE 991,3-Dihydro-3(RS)-[3'-(thiophene)carbonyl]amino-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine

1,3-Dihydro-3(RS)-aminomethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepinehydrobromide (300 mg, 0.59 mmol) and 3-thiophenecarboxylic acid chloride(150 mg, 1.02 mmol) were combined in 50 ml of methylene chloride. Thereaction mixture was immersed in an ice bath and treated withtriethYlamine (330 μl, 2.36 mmol). After addition was complete, stirringwas continued at 0° C. for 10 min. more and then at room temperature for15 min. The reaction mixture was partitioned between methylene chlorideand saturated sodium bicarbonate solution. The phases were separated andthe organic layer was washed with brine, then dried (MgSO₄) andconcentrated under reduced pressure. The crude product (300 mg) waspurified via silica gel chromatography (chloroform-methanol-ammonia,95:5:0.5 v/v, elution) to give the analytical sample.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 379 (M⁺)

Anal. calc'd for C₂₁ H₁₈ FN₃ OS.0.1 CHCl₃ : N, 10.74; C, 64.75; H, 4.66;Found: N, 10.45; C, 64.51; H, 4.82.

EXAMPLE 1001,3-Dihydro-3(RS)-(2'-indolecarbonyl)aminomethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine

1,3-Dihydro-3(RS)-aminomethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepinehydrobromide (300 mg, 0.59 mmol) and 2-indole carboxylic acid chloride(127 mg, 0.70 mmol) were combined in 30 ml of methylene chloride. Thereaction mixture was immersed in an ice bath and treated withtriethylamine (330 μl, 2.36 mmol). After addition was complete, stirringwas continued at 0° C. for 10 min. more and then at room temperature for15 minutes. The reaction mixture was partitioned between methylenechloride and saturated sodium bicarbonate solution. The phases wereseparated and the organic layer was washed with brine, then dried(MgSO₄) and concentrated under reduced pressure. The crude product (220mg) was purified via silica gel chromatography (chloroform-methanolelution, 95:5 v/v) to give the analytical sample.

NMR (CDCl₃ /CD₃ OD): Consistent with the title structure.

MS (14 ev): 412 (M⁺), 252, 239.

Anal. calc'd for C₂₂ H₂₁ FN₄ O.0.15 CHCl₃ : N, 13.01; C, 70.19; H, 4.95;Found: N, 12.70; C, 70.19; H, 5.18.

EXAMPLE 1011,3-Dihydro-3(RS)-(2-L-hydroxy-2-phenylacetyl)aminomethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine

1,3-Dihydro-3(RS)-aminomethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepinehydrobromide (300 mg, 0.59 mmol) and L-mandelic acid (134 mg, 0.88 mmol)were combined in 5 ml of dimethylformamide and treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (169 mg,0.88 mmol). The pH of the resulting reaction mixture was adjusted to 8.5with triethylamine and the reaction was stirred at room temperatureovernight. The solvent was removed under reduced pressure and theresidue was dissolved in ethyl acetate (60ml). The organic phase wasthen washed in succession with sodium bicarbonate solution (3×50 ml) andbrine. The dried (MgSO₄) extracts were concentrated to give 200 mg ofcrude product as a mixture of diastereomers. Preparative thick layerchromatography (chloroform - ethanol - ammonia elution, 90:10:1 v/v)afforded the less polar, faster moving component as a homogeneousanalytical sample.

HPLC: Greater than 98% pure.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 403 (M⁺), 252, 239,212.

Anal. calc'd for C₂₄ H₂₂ FN₃ O₂ 0.5 H₂ O: N, 10.18; C, 69.82; H, 5.62;Found: N, 9.67; C, 69.81; H, 5.55.

EXAMPLE 1021-(2-Cyanoethyl)-1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one(A, 85%) and1-(2-cyanoethyl)-1,3-dihydro-5-(2-fluorophenyl)-3(R)-[1'-(2-cyanoethyl)-3'-indolyl]-methyl-2H-1,4-benzodiazpin-2-one(B, 15%)

The procedure of Example 4 was carried out using acrylonitrile (0.12 g,2,3 mmol) in place of methyl iodide. The chromatographed product, amixture of A (85%) and B (15%) was dried in vacuo at 90°: (m.p. 97°-105°(↑)).

NMR: The spectrum was consistent with the 85:15 mixture of the titlestructure and showed the presence of 0.9 mol of DMF.

HPLC: 96.4% (82.4%+14.0%).

TLC: A single spot (R_(f) =0.22, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂).

MS: Molecular ions at m/e=436 and 489.

Anal. calc'd for 0.85 C₂₇ H₂₁ FN₄ O+0.15 C₃₀ H₂₄ FN₅ O.0.9 C₃ H₇ NO: C,71.07; H, 5.35; N, 13.88; Found: C, 70.95; H, 5.18; N, 13.63.

EXAMPLE 103(2-Carboxyethyl)-1,3-dihydro-5-(2-fluorophenyl)-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using ethyl acrylate (0.22 g,2.2 mmole) in place of methyl iodide. The chromatographed product wasevaporated in vacuo, dissolved in methanol (5 ml), treated with sodiumhydroxide (0.91 ml of 1 M solution), and stirred at room temperaure for24 hours. The mixture was evaporated in vacuo, and the residue wasdissolved in water (10 ml), washed with ether (10 ml), acidified with 1N HCl, and extracted with CH₂ Cl₂ (3×10 ml). The CH₂ Cl₂ layers werewashed with water (1×10 ml), dried over sodium sulfate, filtered, andevaporated to dryness in vacuo. The residue was chromatographed onsilica gel (180:5:1:1 followed by 180:10:1:1 (v/v/v/v) CH₂ Cl₂ :CH₃OH:HoAc:H₂ O) and the product evaporated to dryness in vacuo. Theresidue was dried in vacuo at 40°: (m.p. 75°-90° foam, 130°-160° melt).

TLC: A single spot (R_(f) =0.32, silica gel plate, 180:10:1:1 (v/v/v/v)CH₂ Cl₂ :CH₃ OH:HOAc:H₂ O).

NMR: The spectrum was consistent with the title structure and verifiedthe presence of ether.

HPLC: 99.6% pure.

MS: A molecular ion at m/e=455.

Anal. calc'd for C₂₇ H₂₂ FN₃ O₃.0.55 C₄ H₁₀ O.0.35 H₂ O): C, 69.78; H,5.66; N, 8.36; Found: C, 69.72; H, 5.29; N, 8.07.

EXAMPLE 1041,3-Dihydro-5-(2-fluorophenyl)-3-(2-formylaminobenzoylmethyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3(R)-(3'-indolyl)methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(300 mg, 0.78 mmol) and m-chloroperoxybenzoic acid (85%) (156 mg, 0.90mmol) were combined at room templerature in 20 ml of chloroform. Thereaction mixture was allowed to stand at room temperarure overnight,then was diluted with 30 ml of chloroform and washed with cold,saturated sodium bicarbonate solution. The combined organic extractswere washed with brine, dried (MgSO₄) and concentrated to afford 310 mgof crude product. Silica gel chromatography (hexaneethyl acetate, 1:2v/v) provided the analytical sample.

HPLC: 99% pure.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 415, 397, 369, 267.

Anal. calc'd. for C₂₄ H₁₈ FN₃ O₂.1.0 CHCl₃ : N, 8.10; C, 57.87; H, 3.69;Found: N, 8.09; C, 58.14; H, 3.82.

EXAMPLE 105 1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazeoin-2-one

3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(1.5 gm, 5.57 mmol), indole-2-carbonyl chloride (1.05 gm, 5.85 mmol) andtriethylamine (0.814 ml, 5.85 mmol) were combined in CH₂ Cl₂ (15 ml) andstirred 10 min. The reaction was concentrated and chromatographed onsilica gel (5% MeOH in CH₂ Cl₂) to give the title compound as a whitesolid from CH₂ Cl₂ : (m.p. 290°-291°).

TLC: Silica GF (5% MeOH in CH₂ Cl₂), single homogeneous component.

NMR: Consistent with title structure and verifies the presence of 0.16CH₂ Cl₂.

HPLC: Greater than 99% pure.

M.S.: Mol. ion=412 m/e (free base).

Anal. calc'd for C₂₄ H₁₇ FN₄ O₂.0.16 CH₂ Cl₂ : C, 68.11; H, 4.10; N,13.15; Found: C, 68.06, H, 4.12; N, 12.91.

EXAMPLE 1061,3-Dihydro-3-(RS)-(4-nitrophenlcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmol) and p-nitrobenzoic acid (70 mg, 0.41 mmol) werecombined at room temperature in 5 ml of methylene chloride. To thisreaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (79 mg, 0.41 mmol). The pH of the reaction mixture wasthen adjusted to 8.5 with triethylamine and stirring was continued atroom temperature overnight. The reaction mixture was partitioned betweenmethylene chloride and 10% citric acid solution. The phases wereseparated and the organic layer was washed in succession with 10% citricacid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml)and brine. The dried (MgSO₄) extracts were concentrated to yield 83 mgof crude product. Preparative thick layer chromatography(chloroform-methanol-ammonia, 96:4:0.4 v/v) afforded the analyticalsample (70 mg).

HPLC: Greater than 96.5% pure.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 418 (M⁺), 268, 252.

Anal. calc'd for C₂₂ H₁₅ FN₄ O₄.0.1 CHCl₃ : N, 13.02; C, 61.68; H, 3.54;Found: N, 12.66; C, 61.94; H, 3.74.

EXAMPLE 1071,3-Dihydro-3-(RS)-(2-indolecarbonyloxy)-5-phenyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (100 mg,0.398 mmol) was dissolved in CH₂ Cl₂ (10 ml), treated withindole-2-carbonyl chloride (78.6 mg, 0.438 mmol) and4-dimethylaminopyridine (DMAP, 53.5 mg, 0.438 mmol) and stirred 16 hrs.at 25° C. A second portion of indole-2-carbonylchloride (78.6 mg, 0.438mmol and DMAP (53.5 mg, 0.438 mmol) was added and the reaction stirredan additional 24 hrs. Chromatography of the reaction mixture on silicagel (1% MeOH in CH₂ Cl₂) gave the title compound (100 mg) as a whitesolid from MeCN: (m.p. 271°-273°).

TLC: Silca GF (4% MeOH in CH₂ Cl₂), R_(f) =0.41, single homogeneouscomponent.

NMR: Consistent with title structure.

HPLC: Greater than 98.6% pure.

MS: Molecular ion at m/e=395.

Anal. calc'd for C₂₄ H₁₇ N₃ O₃ : C, 72.90; H, 4.33; N, 10.63; Found: C,72.70; H, 4.31; N, 10.64.

EXAMPLE 108 1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(3-thiophenecarbonylamino)-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(75 mg, 0.229 mmol), thiophene-3-carbonyl chloride (44.9 mg, 0.306 mmol)and triethylamine (42.5 μl, 0.306 mmol) were combined in CH₂ Cl₂ (4 ml)and stirred 10 min. at 25° C. The reaction was concentrated andchromatographed on silica gel (2% MeOH in CH₂ Cl₂) to give the titlecompound as a white solid from Et₂ O: (m.p. 238°-239°).

TLC: Silica GF (5% MeOH in CH₂ Cl₂), R_(f) =0.36, single homogeneouscomponent.

NMR: Consistent with title structure and verifies the presence of 0.05(C₂ H₅)₂ O and 0.70 H₂ O).

HPLC: Greater than 98.8% pure.

MS: Mol. ion=379 m/e (free base).

Anal. calc'd for C₂₀ H₁₄ FN₃ O₂ S. 0.05 (C₂ H₅)₂ O.0.70 H₂ O:

C, 61.30; H, 4.05; N, 10.62; Found: C, 61.24; H, 3.68; N, 10.57.

EXAMPLE 1091,3-Dihydro-3-(RS)-(3-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (49.2 mg,0.196 mmol), indole-3-carboxylic acid (37.9 mg, 0.235 mmol) and 1M DCCin CH₂ C₂ solution (0.235 ml, 0.235 mmol) were mixed in DMF (2 ml) andthe pH adjusted to 9.0 with triethylamine (32.7 μl, 0.235 mmol). Thereaction was stirred 18 hrs. at 25° C., the DMF removed in vacuo, andthe residue chromatographed on a Waters Semi-Prep C-18 30×0.9 cm column(gradient elution of 5 to 95% CH₃ CN in H₂ O) to give the title compoundas a white solid from MeOH/ether: (m.p. 265°-268°).

TLC: Silica GF (90/10/1/1 of CH₂ Cl₂ /MeOH/H₂ O/HOAc), R_(f) =0.57,single homogeneous component.

NMR: Consistent with titlestructure and verifies the presence of 2.0 CH₃OH.

HPLC: 100% pure.

MS: Mol. ion=394 m/e (free base).

Anal. calc'd for C₂₄ H₁₈ N₄ O₂.2CH₃ OH: C, 68.10; H, 5.72; N, 12.22;Found: C, 68.19; H, 4.62; N, 12.50.

EXAMPLE 1101,3-Dihydro-3-(RS)-(4-thianaPhtheneacetyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmol) and 4-thianaptheneacetic acid (79 mg, 0.41 mmol)were combined at room temperature in 5 ml of methylene chloride. To thisreaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (79 mg, 0.41 mmole). The pH of the reaction mixture wasthen adjusted to 8.5 with triethylamine and stirring was continued atroom temperature overnight. The reaction mixture was partitioned betweenmethylene chloride and 10% citric acid solution. The phases wereseparated and the organic layer was washed in succession with 10% citricacid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml)and brine. The dried (MgSO₄) extracts were concentrated to yield 130 mgof crude product. Preparative thick layer chromatography(chloroform-methanol-ammonia, 95:5:0.5 v/v) afforded the analyticalsample, m.p. 259°-260° C.

NMR (CDCl₃): consistent with the title structure. MS (14 ev): 443 (M⁺),268, 174.

Anal. calc'd for C₂₅ H₁₈ FN₃ O₂ S.0.075 CHCl₃ : N, 9.28; C, 66.56; H,4.02; Found: N, 9.10; C, 66.53; h, 4.11.

EXAMPLE 1111,3-Dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmol) and p-chlorobenzoyl chloride (52 μl, 0.41 mmole)were combined at room temperature in 5 ml of methylene chloride. Theresulting solution was protected from moisture and stirred at roomtemperature overnight. The reaction mixture was diluted with 70 ml ofmethylene chloride and washed with sodium bicarbonate solution (sat.)and brine. The organic extracts were dried (MgSO₄) and concentrated togive 150 mg of crude product. Chromatography on silica gel(chloroform-methanol-ammonia, 95:5:0.5 v/v) and trituration with hexaneyielded the analytical product as a white powder, m.p. 258°-259° C.

HPLC: Greater than 98% pure.

NMR: (CDCl₃): Consistent with the title structure.

MS (14 ev): 407 (M⁺), 268, 252, 241.

Anal. calc'd for C₂₂ H₁₅ ClFN₃ O₂.0.2 CHCl₃ : N, 9.73; C, 61.76; H,3.55; Calc'd: N, 9.34; C, 61.65; H. 3.68.

EXAMPLE 1121,3-Dihydro-3-(RS)-(4-methylphenylsulfonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(116 mg, 0.43 mmole) and p-toluenesulfonyl chloride (82 mg, 0.43 mmole)were combined at room temperature in 5 ml of methylene chloride. The pHof the reaction mixture was then adjusted to 8.5 with triethylamine andstirring was continued at room temperature overnight. The reactionmixture was partitioned between methylene chloride and 10% citric acidsolution. The phases were separated and the organic layer was washed insuccession with 10% citric acid solution (1×30 ml), saturated sodiumbicarbonate solution (2×30 ml) and brine. The dried (MgSO₄) extractswere concentrated to yield 200 mg of crude product. Recrystallizationfrom ethyl acetate afforded the analytical sample as white needles, m.p.215°-216° C. HPLC: Greater than 99% pure.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 359, 316, 268, 241, 225, 212, 92.

Anal. calc'd for C₂₂ H₁₈ FN₃ O₃ S.0.1C₄ H₈ O₂ : N, 9.72; C, 62.23; H,4.38; Found: N, 9.64; C, 61.92 H, 4.31.

EXAMPLE 1131-Carboxymethyl-1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was carried out using1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one(0.92 g, 2.2 mmole) in place of1,3-dihydro-5-(2-fluorophenyl)-3-(R)-(3'-indolyl)-methyl-2H-1,4-benzodiazepin-2-one,and ethyl bromoacetate (0.38 g, 2.25 mmol) in place of methyl iodide.The chromatographed product (10% ether in CH₂ Cl₂) (0.05 g, 0.098 mmol)and sodium hydroxide (0.14 ml, 1N, 0.14 mmol) were stirred together inCH₃ OH (3 ml) at room temperature for 36 hours. The mixture wasconcentrated in vacuo, diluted to 5 ml with H₂ O, made acidic with 1 NHCl, and extracted with CH₂ Cl₂ (3×5 ml). The organic layers werecombined, washed with water (1×5 ml), dried over Na₂ SO₄, filtered, andevaporated to dryness in vacuo. The residue was crystallized fromacetone (0.1 ml) and Et₂ O (2 ml) and the solid dried in vacuo at 60°;(m.p. 278°-278.5° (d)).

TLC: A single spot (R_(f) 0.27, silica gel plate, 180:10:1:1 (v/v/v/v)CH₂ Cl₂ :CH₃ OH:HOAc:H₂ O).

NMR: The spectrum was consistent with the title structure and verifiedthe presence of ether and acetone.

HPLC: 99.4% pure.

MS: A molecular ion at m/e=470.

Anal. calc'd for C₂₆ H₁₉ FN₄ O₄ 0.6C₃ H₆ O .0.2C₄ H₁₀ O.0.8 H₂ O: C,64.25; H, 4.94; N, 10.48; Found: C, 64.29; H, 4.56; N, 10.23.

EXAMPLE 1141,3-Dihydro-3-(RS)-(5-fluoroindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.398 mmol) was suspended in 2 ml of methylene chloride.5-fluoroindole-2-carboxylic acid chloride (87 mg, 0.438 mmol) was addedto the methylene chloride suspension. The pH of the stirred mixture wasadjusted to 9 with 100 μl of triethylamine. The reaction mixture wasstirred for 24 hours. The mixture was then diluted with 1 ml of methanoland filtered. The filtrate was pipeted onto a 2000μ Analtech preparativeTLC plate which was developed in a 95:5:0.5 chloroform, methanol, water(CMW) solvent system. The product band was collected. The silica waswashed with 90:10:1 CMW. The filtrate was evaporated and the residue wasdissolved in methanol and placed in a small vial. The solvent wasevaporated to yield 15.2 mg of product.

HPLC: 90% pure.

MS: M⁺ (14 ev), m/e 430.

NMR: Consistent with title product.

Anal. calc'd for C₂₄ H₁₆ F₂ N₄ O₂ 1.6CH₃ OH: N, 11.63; C, 63.83; H,4.65; Found: N, 11.66; C, 63.84; H, 3.72.

EXAMPLE 1151,3-Dihydro-3-(RS)-(3'-methylindenyl-2-carbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmol) and 3-methylindene-2-carboxylic acid (70 mg, 0.40mmol) were combined at room temperature in 5 ml of methylene chloride.To this reaction mixture was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.41mmol). The pH of the reaction mixture was then adjusted to 8.0 withtriethylamine and stirring was continued at room temperature overnight(19 hours). The reaction mixture was partitioned between methylenechloride and 10% citric acid solution. The phases were separated and theorganic layer was washed in succession with 10% citric acid solution(1×30 ml), saturated sodium bicarbonate solution (2×30 ml), and brine.The dried (MgSO₄) extrcts were concentrated to yield 130 mg of crudeproduct. Preparative thick layer chromatography (hexane-ethyl acetate,1:1 v/v) afforded the analytical sample.

HPLC: Greater than 98% pure.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 425 (M⁺), 268, 199, 156.

Anal. calc'd for C₂₆ H₂₀ FN₃ O₂.1.25 H₂ O: N, 9.38; C, 69.70; H, 5.06;Found: N, 8.86; C, 69.75; H, 4.85.

EXAMPLE 1161,3-Dihydro-3-(RS)-(2-quinaldyl)amino-5-(2-fluorophenyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmol) and 2-quinoline carboxylic acid (quinaldic acid) (70mg, 0.40 mmol) were combined at room temperature in 5 ml of methylenechloride. To this reaction mixture was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (76 mg, 0.40mmole). The pH of the reaction mixture was then adjusted to 8.5 withtriethylamine and stirring was continued at room temperature for 48hours. The reaction mixture was partioned between methylene chloride and10% citric acid solution. The phases were separated and the organiclayer was washed in succession with 10% citric acid solution (1×30 ml),saturated sodium bicarbonate solution (2×30 ml) and brine. The dried(MgSO₄) extracts were concentrated to yield 150 mg of crude product.Preparative thick layer chromatography (chloroform-methanol-ammonia,97:3:0.3 v/v) afforded the analytical sample (60 mg).

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 424 (M⁺), 268, 241, 198, 184.

Anal. calc'd for C₂₅ H₁₇ FN₄ O₂.0.75 H₂ O: N, 12.79; C, 68.56; H, 4.25;Found: N, 13.35; C, 68.53; H, 4.23.

EXAMPLE 1171,3-Dihydro-3-(RS)-(2-L-hydroxy-2-phenylacetyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmol) and L-mandelic acid (63 mg, 0.41 mmol) were combinedat room temperature in 10 ml of methylene chloride. To this reactionmixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (79 mg, 0.41 mmol). The pH of the reaction mixture wasthen adjusted to 8.5 with triethylamine and stirring was continued atroom temperature for 96 hours. The reaction mixture was partitionedbetween methylene chloride and 10% citric acid solution. The phases wereseparated and the organic layer was washed in succession with 10% citricacid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml)and brine. The dried (MgSO₄) extracts were concentrated to yield 130 mgof crude product as a mixture of diastereomers. Preparative thick layerchromatography (chloroform-methanol-ammonia, 95:5:0.5, v/v) afforded theanalytical sample.

NMR (CDCl₃): consistent with the title structure.

EXAMPLE 1181,3-Dihydro-3-(RS)-(5-Chloroindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.391 mmol) was suspended in 2 ml of methylene chloride.5-Chloroindole-2-carboxylic acid chloride (86.7 mg, 0.438 mmol) wasadded. The pH of the stirred mixture was adjusted to 9 withtriethylamine (95 μl ). The reaction mixture was stirred for 24 hours.The mixture was then diluted with 1 ml of methanol and filtered. Thefiltrate was pipeted onto a 2000μ Analtech preparative TLC plate whichwas developed in a 95:5:0.5 chloroform, methanol, water (CMW) solventsystem. The product band was collected. The silica was washed with90:10:1 CMW. The filtrate was evaporated and the residue was dissolvedin methanol and placed in a small vial. The solvent was evaporated toyield 16.4 mg of purified product.

HPLC: 90% pure.

MS (14 ev): (M⁺) m/e 446.

NMR: Consistent with title product.

Anal. calc'd for C₂₄ H₁₆ Cl₁ FN₄ O₂.0.8CH₃ OH C, 63.04; H, 4.09; N,11.86; Found: C, 63.03; H, 3.66; N, 11.58.

EXAMPLE 1193-(RS)-[N-(2-indolecarbonyl)-N-methylamino]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-methylamino-5-phenyl-2H-1,4-benzodiazepin-2-one (130mg, 0.49 mmol) and indole-2-carbonyl chloride (88 mg, 0.49 mmol) werecombined in CH₂ Cl₂ (5 ml) and stirred 2 hours at 25° C. The reactionwas concentrated and chromatographed on silica gel (3% MeOH in CH₂ Cl₂)to give the title compound as a white solid from CH₂ Cl₂ : (m.p.287°-288.5°).

TLC: Silca GF (5% MeOH in CH₂ Cl₂), R_(f) =0.41, single homogeneouscomponent.

NMR: Consistent with title structure and verified the presence of 0.25H₂ O.

HPLC: Greater than 97.2% pure.

MS: Mol. ion=408 m/e (free base).

Anal. calc'd for C₂₅ H₂₀ N₄ O₂.0.25H₂ O: C, 72.70; H, 5.00; N, 13.57;Found: C, 72.64; H, 4.87; N, 13.30.

EXAMPLE 1201,3-Dihydro-3-(RS)-(5-Bromoindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

The procedure of Example 114 was carried out using5-bromoindole-2-carboxylic acid chloride (0.113 g, 0.438 mmole) in placeof 5-fluoroindole-2-carboxylic acid chloride.

HPLC: 82% pure.

MS: M⁺ (14 ev) , m/e 490.

NMR: Consistent with title product.

Anal. calc'd for C₂₄ H₁₆ BrFN₄ O₂.0.28CHCl3: N, 10.68; C, 55.57; H,3.13; Found: N, 10.31; C, 55.98; H, 3.36.

EXAMPLE 1213-(RS)-Cinnamoylamino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-(2'-fluorophenyl)-2H-1,4-benzodiazepin-2-one(50 mg, 0.186 mmol) was suspended in methylene chloride (1 ml).Cinnamoyl chloride (34.5 mg, 0.207 mol) was added to the methylenechloride mixture. The pH of the stirred mixture was adjusted to ˜9 with50 μl of triethylamine. After stirring for 16 hours the mixture wasfiltered. The product in the filtrate was purified by prep TLC. Theproduct band was collected by washing the silica containing the product,with 80:20:2 CMW. The solvent was evaporated and the residue wasdissolved in methanol, placed in a small vial and evaporated. Yield 16.6mg.

HPLC: 97% Pure.

MS: M⁺ (14 ev) m/e 399

NMR: Consistent with title structure.

Anal. calc'd for C₂₄ H₁₈ FN₃ O₂.0.126CHCl₃ N, 10.18; C, 70.24; H, 4.42;Found: N, 10.08; C, 70.07; H, 4.46.

EXAMPLE 1221,3-Dihydro-3-(RS)-(5-hydroxy-2-indolylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmole) and 5-hydroxyindole-2-carboxylic acid (75 mg, 0.44mmole) were combined at room temperature in a mixture of 1 ml ofdimethylformamide and 5 ml of methylene chloride. To this reactionmixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (76 mg, 0.40 mmol). The pH of the reaction mixture wasthen adjusted to 8.5 with triethylamine and stirring was continued atroom temperature for 48 hours. The solvent was removed under reducedpressure and the residue was partitioned between ethyl acetate and 10%citric acid solution. The phases were separated and the organic layerwas washed in succession with 20% citric acid solution (1×30 ml),saturated sodium bicarbonate solution (2×30 ml) and brine. The dried(MgSO₄) extracts were concentrated to yield 200 mg of the product.Preparative thick layer chromatography (chloroform-ethanol-ammonia,90:10:1, v/v) afforded the analytical sample (80 mg).

NMR (CD₃ OD): Consistent with the title structure.

MS (14 ev): 428 (M⁺), 227, 176, 159.

Anal. calc'd. for C₂₄ H₁₇ FN₄ O₃.0.25 CHCl₃ : N, 12.23; C, 63.56; H,3.79; Found: N, 12.09; C, 63.99; H, 4.09.

EXAMPLE 1231-Carboxamidomethyl-1,3-dihydro-3R-(3-indolylmethyl)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3R-(3-indolylmethyl)-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(10 g, 16 mmol) was stirred in 120 ml of degassed DMF at 0° C. undernitrogen with sodium hydride (1.25 g, 26 mmol) until homogeneous (1hour). Ethylbromoacetate (2.88 ml, 26 mmol) was added and the reactionmixture was stirred at room temperature for 1 hour. The reaction wasquenched in 1 l of water. The aqueous solution was extracted with 3×250ml of methylene chloride. The methylene chloride solution was washedwith 250 ml water. The organic phase was separated, dried over sodiumsulfate and concentrated in vacuo.

A portion of the crude ester (530 mg) was dissolved in 50 ml ofmethanol. The solution was stirred in a pressure bottle and saturatedwith ammonia at 0° C. The bottle was sealed and the solution was stirredat room temperature for 48 hours. The solution was concentrated invacuo. This gave a solid which was purified by flash chromatogrphy in a97:3 chloroform/methanol solvent system to 245 mg of purified product.

HPLC: 99% pure.

MS: M⁺ (14 ev) m/e 440

NMR: Consistent with title structure.

Anal. calc'd for C₂₆ H₂₁ FN₄ O₂.0.53H₂ O: N, 12.45; C, 69.39; H, 4.82;Found: N, 12.27; C, 69.32; H, 4.80.

EXAMPLE 1241,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indolylmethyl-amino)-2H-1,4-benzodiazepin-2-one

3-(RS)-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(150 mg, 0.520 mmol) and 2-aminomethylindole (75.9 mg, 0.520 mmol) werecombined in 1,2-dimethoxyethane (3 ml) and the mixture stirred 20 min.at 25° C. The mixture was evaporated to dryness in vacuo and the residuetreated with H₂ O and extracted with EtOAc (3x). The combined extractswere washed with H₂ O (1X), dried over MgSO₄, filtered and stripped todryness in vacuo to give an orange oil which, after chromatography onsilica gel (4% MeOH in CH₂ Cl₂) provided the title compound as a whitesolid from ether: (m.p. 200°-202°).

TLC: Silica GF (5% MeOH in CH₂ Cl₂), R_(f) =0.37, single homogeneouscomponent.

NMR: Consistent with title structure.

HPLC: Greater than 97.7% pure.

MS: Molecular ion at m/e=398.

Anal. calc'd for C₂₄ H₁₉ FN₄ O: C, 72.35; H, 4.81; N, 14.06; Found: C,72.48; H, 4.81; N, 13.69.

EXAMPLE 1251,3-Dihydro-3-(RS)-(phenylaminomethylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(100 mg, 0.37 mmol) and N-phenyl glycine (64 mg, 0.42 mmol) werecombined at room temperature in 5 ml of methlylene chloride. To thisreaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (81 mg, 0.42 mmole). The pH of the reaction mixture wasthen adjusted to 8.5 with triethylamine and stirring was continued atroom temperature overnight. More N-phenylglycine and carbodiimidereagent were added (0.2 equivalents) and stirring was continued. Thereaction mixture was partitioned between methylene chloride and 10%citric acid solution after 48 hours reaction time. The phases wereseparated and the organic layer was washed in succession with 20% citricacid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml)and brine. The dried (MgSO₄) extracts were concentrated to yield 200 mgof crude product. Preparative thick layer chromatography(chloroform-ethanol-ammonia 92:8:0.8 v/v) afforded the analytical sample(100 mg), m.p. 145°-146°.

NMR (CDCl₃). Consistent with the title structure.

MS (14 ev): 402 (M⁺), 265.

Anal. calc'd for C₂₃ H₁₉ FN₄ O₂.0.55 CHCl₃ : N, 11.97; C, 60.43; H,4.21; Found: N, 11.80; C, 60.37; H, 4.06.

EXAMPLE 1261,3-Dihydro-3-(RS)-(5-methoxyindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(50 mg, 0.186 mmol) was suspended in 1 ml of methylene chloride.5-Methoxyindole-2-carboxylic acid (36.9 mg, 0.207 mmol) was added to thesuspension followed by the addition of 38.5 mg (0.2 mmol) of EDC. Themixture was brought to pH 8 with 60 μl of triethylamine. The solid whichformed after 3 min. was filtered after 5 hours and washed withchloroform. The filtrate was applied to a 2000μ preparative TLC plateand eluted with 90:10:1 chloroform:methanol:water (CMW). The product wasextracted from silica with methanol and evaporated.

HPLC: 98% pure.

MS: M⁺ (14 ev) m/e 442

NMR: Consistent with title structure.

Anal. calc'd for C₂₅ H₁₉ FN₄ O₃.0.1CHCl₃ : N, 12.33; C, 66.34; H, 4.24;Found: N, 10.59; C, 66.19; H, 4.23.

EXAMPLE 1271,3-Dihydro-3-(RS)-(1-methylindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one

3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(50 mg, 0.186 mmol) was suspended in 1 ml of methylene chloride.1-Methylindole-2-carboxylic acid (36.2 mg, 0.2 mmol) was added to thesolution followed by the addition of 8.5 mg (0.2 mmol) of EDC. The pH ofthe solution was brought to 8 with 60 μl of triethylamine. Afterstirring for 4 hours the product was purified by preparative TLC on a2000μ silica gel plate with a 95:5:0.5 chloroform/methanol/water solventsystem. The product band was collected and isolated by washing thesilica with 90:10:1 CMW. yield 16.5 mg.

HPLC: 99% pure

MS: M³⁰ (14 ev) m/e 426

NMR: Consistent with title structure.

Analysis calc'd for C₂₅ H₁₉ FN₄ O₂ . 0.8CH₃ OH: N, 12.39; C, 68.54; H,4.95; Found: N, 12.34; C, 68.29; H, 4.18.

EXAMPLE 1281,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-benzofurancarbonylamino)-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(80 mg, 0.297 mmol), benzofuran-2-carboxylic acdd (48 mg, 0.297 mmol),and EDC (56.9 mq. 0.297 mmol) were combined in CH₂ Cl₂ (3 ml) and the pHadjusted to 9.5 with triethylamine (41 μl, 0.297 mmol). After stirring30 minutes at 25° C., the reaction was concentrated and chromatographedon silica gel (3% MeOH in CH₂ Cl₂) to give the title compound as a whitesolid from CH₂ Cl₂ /Et₂ O: (m.p. 289°-291°).

TLC: Silica GF (5% MeOH in CH₂ Cl₂), R_(f) =0.48, single homogeneouscomponent.

NMR: Consistent with title structure and verified the presence of 0.15CH₂ Cl₂ and 0.1 (C₂ H₅)₂ O.

HPLC: Greater than 99.7% pure.

M.S.: Mol. ion=413 m/e (free base).

Anal. Calc'd for C₂₅ H₁₆ FN₃ O₃. 0.15 CH₂.0.10 (C₂ H₅)₂ O: Calc'd: C,68.01; H, 4.02; N 9.69; Found: C, 68.22; H, 3.86; N, 9.36.

EXAMPLE 1291-Ethoxycarbonylmethyl-1,3-dihydro-3(RS)-(4-chloro-phenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

To a suspension of sodium hydride (50%) (24.4 mg, 0.51 mmole) in 2 ml ofdry dimethylformamide at 0° C. was added, under nitrogen,1,3-dihydro-3(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(197.3 mg, 0.48 mmole). The resulting reaction mixture becamehomogeneous over a one-hour period, was stirred one hour more at 0° C.and then treated with ethylbromoacetate (55 μl, 0.50 mmole). Thereaction mixture was warmed to room temperature and after one hour wasquenched with brine. The aqueous mixture was extracted with ethylacetate and the combined organic extracts were washed with brine.Rotoevaporation of the dried extracts (MgSO₄) gave a semi-solid whichwas chromatographed on silica gel (chloroform-methanol-ammonia 95:5:0.5v/v elution) to afford 64 mg of the analytical sample. mp 172° (soften),177°-178° C.

NMR (CDCl₃): Consistent with the title structure.

MS (14 ev): 493 (M⁺), 364, 354, 338, 327, 313

Analysis calc'd for C₂₆ H₂₁ ClFN₃ O₄. 0.1 C₄ H₈ O₂ : N, 8.35; C, 63.05;H, 4.32; Found: N, 8.16; C, 62.89; H, 4.44.

EXAMPLE 1301,3-Dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one (500 mg,1.98 mmole) and p-chlorobenzoyl chloride (255 μl, 2.00 mmole) werecombined at room temperature in 30 ml of methylene chloride. Theresulting solution was protected from moisture and stirred at roomtemperature overnight. The reaction mixture was diluted with 70 ml ofmethylene chloride and washed with sodium bicarbonate solution (sat.)and brine. The organic extracts were dried (MgSO₄) and concentrated togive the crude product. Trituration with ether afforded the analyticalsample as a white solid.

NMR (CDCl₃). Consistent with the title structure.

MS (14 ev): 389((M⁺), 250, 234.

Analysis calc'd for: C₂₂ H₁₆ ClN₃ O₂ : N, 10.78; C, 67.78; H, 4.13;Found: N, 10.71; C, 67.79; H, 3.97.

EXAMPLE 1311,3-Dihydro-1-methyl-3-(RS)-(4-chlorophenylcarbonyl)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one

To a suspension of sodium hydride (50%) (10 mg, 0.21 mmole) in 1 ml ofdry dimethylformamide at 0° C. was added, under a nitrogen,1,3-dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one(65.5 mg, 0.166 mmole). The resulting reaction mixture becamehomogeneous over a one-hour period, was stirred one hour more at 0° C.and then treated with iodomethane (10.8 μl, 0.17 mmole). The reactionmixture was warmed to room temperature and after one hour was quenchedwith brine. The aqueous mixture was extracted with ethyl acetate and thecombined organic extracts were washed with brine. Rotoevaporation of thedried extracts (MgSO₄) gave a semi-solid which was chromatographed onsilica gel (chloroform-methanol-ammonia 95:5:0.5 v/v elution) to givethe analytical sample.

NMR (CDCl₃). Consistent with the title structure;

MS (14 ev): 403 (M⁺)

Analysis calc'd for: C₂₃ H₁₈ ClN₃ O₂ : N, 10.40; C, 68.40; H, 4.49;Found: N, 10.11; C, 68.50; H, 4.57.

EXAMPLE 1321-Carboxymethyl-1,3-dihydro-3-(RS)-(4-chlorophenyl-carbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

To a suspension of sodium hydride (50%) (14.0 mg, 0.30 mmole) in 2 ml ofdry dimethylformamide at 0° C. was added, under nitrogen,1,3-dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(103.0 mg, 0.25 mmole). The resulting reaction mixture becamehomogeneous over a one-hour period, was stirred one hour more at 0° C.and then treated with 1 ml of dimethylformamide containing sodiumiodoacetate (56 mg) (0.27 mmole). The reaction mixture was warmed toroom temperature and after 12 hours was quenched with brine. The aqueousmixture was extracted with ethyl acetate and the combined organicextracts were washed with brine. Rotoevaporation of the dried extracts(MgSO₄) gave a semi-solid which was chromatographed on silica gel(chloroform-methanol-acetic acid, 93:6:1 v/v) to provide the analyticalsample: (m.p. 225°-228° C., from methanol).

FABMS: m/e=466 (M+H), 245, 177

NMR (DMSO-d₆): consistent with title structure.

Anal. Calc'd for C₂₄ H₁₇ ClFN₃ O₄ 0.45NaI 0.75 H₂ O: C, 52.71; H, 3.41;N, 7.68. Found: C, 52.87; H, 3.64; N, 7.43.

EXAMPLE 1331,3-Dihydro-3-(RS)-(2-indolinecarbonylamino)-5-phenyl-2-H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (100 mg,0.398 mmol), 1-indoline-2-carboxylic acid (64.9 mg, 0.398 mmol),1-hydroxybenzotriazole hydrate (HBT, 53.8 mg, 0.398 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 76.3mg, 0.398 mmol) were combined in DMF (2 ml) and the pH of the solutionwas adjusted to 9.0-9.5 with triethylamine (TEA, 95, 1, 0.683 mmol).After stirring 15 minutes at 25° C., the DMF was removed in vacuo, theresidue treated with H₂ O and extracted with EtOAc (3x). The combinedorganic extracts were washed with brine, dried over MgSO₄, filtered andstripped to dryness in vacuo to give a white solid (180 mg). Flashchromatography on silica gel (267/10/1 of CH₂ Cl₂ /MeOH/concentrated NH₄OH) gave a white solid (38 mg) from EtOAc/hexane. The product is asingle stereoisomer whose absolute configuration is unknown; m.p. 252°-272° C. (slowly shrinkes to a cloudy melt).

TLC: Silica GF (190/10/1 of CH₂ Cl_(2/) MeOH/ concentrated NH₄ OH),R_(f) =0.40, single, clean component.

NMR: Consistent with title structure and verifies the presence of EtOAc.

HPLC: Greater than 96% pure.

MS: Molecular ion at m/e=396.

Anal. calc'd for C₂₄ H₂₀ N₄ O₂ . 0.45C₄ H₈ O₂ : C, 71.06; H, 5.46; N,12.85; Found: C, 70.71; H, 5.11; N, 13.20.

EXAMPLE 1341,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(p-trifluoro-methylbenzoylamino)-2H-1,4-benzodiazepin-2-one

1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one(42 mg, 0.156 mmole) and p-trifluoromethylbenzoyl chloride (32.5 mg,0.156 mmole) were combined in 3 ml of methylene chloride (CH₂ Cl₂),treated with triethylamine (0.0157 g, 0.156 mmole) and stirred at roomtemperature 15 minutes. The mixture was diluted with CH₂ Cl₂ (20 ml),washed with 10% citric acid (2×5 ml), dilute sodium bicarbonate (2×5ml), and water (2×5 ml), dried over sodium sulfate, filtered, andevaporated to dryness in vacuo. The residue was crystallized from ethylacetate (0.4 ml)/ether (1 ml) to give the title compound which was driedin vacuo at 90°: (m.p. 209°-211°).

TLC: Single spot, R_(f) =0.62, silica gel plate, 90:10:1:1 (v:v:v:v) CH₂Cl₂ :MeOH:HOAc:H₂ O.

NMR: The spectrum was consistent with the title structure and verifiedthe presence of EtOAc.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=441.

Anal. calc'd for C₂₃ H₁₅ F₄ N₃ O₂.0.2EtOAc: C, 62.27; H, 3.64; N, 9.16;Found: C, 62.25; H, 3.61; N, 9.11.

EXAMPLE 1351,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(p-methylbenzoylamino)-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using p-methylbenzoylchloride (24 mg, 0.156 mmole) in place of p-trifluoromethylbenzoylchloride. The title compound was crystallized from CH₂ Cl₂ (3 ml)/Et₂O(1 ml) and dried in vacuo at 90°: (m.p. 275°-276° (d)).

TLC: Single spot, R_(f) =0.62, silica gel plate, 90:10:1:1 (v:v:v:v) CH₂Cl₂ :MeOH:HOAc:H₂ O.

NMR: The spectrum was consistent with the title structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=387.

Anal. calc'd for C₂₃ H₁₈ FN₃ O₂. 0.4H₂ O: C, 70.00; H, 4.80; N, 10.65;Found: C, 70.04; H, 4.68; N, 10.56.

EXAMPLE 1361,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(p-methoxybenzoylamino)-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using p-methoxybenzoylchloride (26.6 mg, 0.156 mmole) in place of p-trifluoromethylbenzoylchloride. The title compound was crystallized from CH₂ Cl₂ (2 ml)/Et₂ O(1 ml) and dried in vacuo at 90°: (m.P. 231°-233°).

TLC: Single spot, R_(f) =0.47, silica gel plate, 5% (v/v) MeOH/CH₂ Cl₂.

NMR: The spectrum was consistent with the title structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=403.

Anal. calc'd for C₂₃ H₁₈ FN₃ O₃ : C, 68.48; H, 4.50; N, 10.42; Found: C,68.62; H, 4.60; N, 10.36.

EXAMPLE 1373-(RS)-(o-Chlorobenzoylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (250 mg,0.93 mmol) was suspended in methylene chloride (10 ml) and treated witho-chlorobenzoylchloride (0.124 ml, 0.97 mmol) followed by triethylamine(0.143 ml, 0.97 mmol). The solution was stirred at room temperatureovernight. The reaction solution was chromatographed on silica gel(chloroform followed by 97/3 chloroform/methanol) and the combinedproduct fractions were evaporated to dryness in vacuo. TLC: Silica gel(90:10:1, CHCl₃ :CH₃ OH:H₂ O), R_(f) =0.85.

NMR: Consistent with structure.

HPLC: 99% pure.

MS: Molecular ion at m/e=389.

Anal. calc'd for Chd 22H₁₆ ClN₃ O₂ : C, 67.78; H, 4.14; N, 10.77; Found:C, 67.34; H, 4.00; N, 10.72.

EXAMPLE 1383-(RS)-(N-(o-Chlorobenzoyl)-N-methylamino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-1,3-Dihydro-(o-Chlorobenzoylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one(200 mg, 0.51 mmol) and sodium hydride (52 mg of a 50% suspension inmineral oil, 1.094 mmol) were stirred in 2 ml of dry, degasseddimethylformamide under nitrogen in an ice bath. The mixture was stirreduntil homogeneous. After 2 hours, methyl iodide (38 μl, 1.094 mmol) wasadded in one portion. The reaction was stirred for 1 hour at 0° C. and 1hour at room temperature. The reaction was quenched with 3 ml ofsaturated sodium chloride solution. The mixture was extracted with ethylacetate. The clear solution obtained when chloroform was added wasevaporated to dryness then chromatographed on silica gel with chloroformas the elution solvent. The 7:1 mixture of the di and mono substitutedcompounds was further purified by Preparative TLC. (Analtech silica gel2000μ prep TLC plates developed twice in a 98:2 chloroform/methanolsolvent system).

TLC: Silica gel 97:2 CHCl₃ :MeOH, R_(f) =0.35.

NMR: Consistent with structure.

MS: Molecular ion m/e=417

HPLC: 98%.

Anal. calc'd for C₂₄ H₂₀ ClN₃ O₂ 0.35CHCl₃ : C, 63.62; H, 4.46; N, 9.14;Found: C, 63.40; H, 4.55; N, 8.97.

EXAMPLE 1393-(RS)-(o-Chlorobenzoylamino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(RS)-1,3-Dihydro-(o-Chlorobenzoylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one(207 mg, 0.53 mmol) and sodium hydride (26 mg of a 50% suspension inmineral oil, 0.54 mmol) were stirred in 2 ml of dry, degasseddimethylformamide under nitrogen in an ice bath. The mixture was stirreduntil homogenous. After 2 hours, methyl iodide (34 μl, 0.547 mmol) wasadded in one portion. (The remainder of the experiment proceeds asdescribed in Example 139).

NMR: Consistent with structure.

HPLC: 98%.

MS: Molecular ion m/e 403.

Anal. calc'd for C₂₃ H₁₈ ClNpghd 3O₂ 0.62H₂ O: C, 66.56; H, 4.67; N,10.12; Found: C, 66.71; H, 4.53; N, 9,90.

EXAMPLE 1403-(RS)-(m-Chlorobenzoylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 137 was carried out using m-chlorobenzoylchloride in place of o-chlorobenzoylchloride. The reaction waschromatographed using chloroform as the elution solvent.

TLC: Silica gel 90:10:1 CMA; R_(f) =0.8.

NMR: Consistent with structure.

HPLC: 96%.

MS: Molecular ion at m/e 389.

Anal. calc'd for C₂₂ H₁₆ N₃ O₂ 0.62CHCl₃ : C, 59.86; H, 3.69; N, 9.30;Found: C, 59.99; H, 3.75; N, 9.18.

EXAMPLE 1413-(RS)-(3,4-Dichlorobenzoylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The EDC procedure in Example 126 was carried out using3,4-dichlorobenzoic acid in place of 5-methoxy-indole-2-carboxylic acid.The reaction product was dissolved in chloroform and chromatographedwith chloroform followed by 99:1 CHCl₃ :MeOH(CM).

TLC: Silica gel 97:3 CM, R_(f) =0.45.

HPLC: 100%.

NMR: Consistent with structure.

MS: Molecular ion at m/e 423.

Anal. calc'd for C₂₂ H₁₅ Cl₂ N₃ O₂ 0.08CHCl₃ C, 61.12; H, 3.50; N, 9.69;Found: C, 61.05; H, 3.50; N, 9.30.

EXAMPLE 1423-(RS)-(p-Chlorobenzoylamino)-1,3-dihydro-5-(2'-fluorophenyl)-1-methyl-4-oxo-2H-1,4-benzodiazepin-2-one

3-(RS)-(p-Chlorobenzoylamino)1,3-Dihydro-5-(2'-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(50 mg, 0.118 mmol) was stirred in 3 ml of chloroform.m-Chloroperoxybenzoic acid (23.6 mg, 0.137 mmol) was added. Afterstirring overnight another 23.6 mg of MCPBA was added. The solution wasstirred for 48 hours then diluted with chloroform and washed with coldsaturated sodium bicarbonate. The chloroform solution was dried oversodium sulfate and evaporated. The residue obtained after evaporationwas purified by preparative TLC with 98:2 CHCl₃ :MeOH (CM) as thedeveloping solvent.

TLC: Silica gel 98:2 CM, R_(f) =0.4 CM.

NMR: Consistent with structure.

HPLC: 95%.

MS: Molecular ion at m/e=437.

Anal. calc'd for C₂₃ H₁₇ ClFN₃ O₃ 0.05CHCl₃ : C, 62.37; H, 3.87; N,9.46; Found: C, 62.41; H, 3.80; H, 9.43.

EXAMPLE 1431,3-Dihydro-5-Phenyl-3-(RS)-(4'-methylthiobenzoylamino)-2H-1,4-benzodiazepin-2-one

The EDC procedure in Example 126 was carried out using 4-methylthiobenzoic acid in place of 5-methoxyindole-2-carboxylic acid. Thereaction solution was chromatographed on a silica gel column withchloroform followed by 99:1 CHCl₃ :MeOH (CM).

TLC: Silica gel 97:3 CM, R_(f) =0.3

NMR: Consistent with structure.

HPLC: 97%.

MS: Molecular ion at m/e 401.

Anal. calc'd for C₂₃ H₁₉ N₃ O₂ S 0.65CHCl₃ : C, 59.28; H, 4.13; N, 8.77;Found: C, 59.33; H, 4.21; N, 8.57.

EXAMPLE 1441-3-Dihydro-3-(RS)-(4'-fluorobenzoylamino)-5-phenyl-2H-1,4-benzodiazeoin-2-one

The procedure of Example 137 was carried out using 4-fluorobenzoylchloride in place of o-chlorobenzoyl chloride. The reaction waschromatographed on silica gel using chloroform as the elution solvent.

TLC: Silica gel 97:3 CHCl₃ :MeOH (CM), R_(f) =0.33.

NMR: Consistent with structure.

HPLC: 95%.

MS: Molecular ion at m/e 373.

Anal. calc'd for C₂₂ H₁₆ FN₃ O₂ 0.2H₂ O: C, 70.09; H, 4.39; N, 11.15;Found: C, 70.14; H, 4.36; N, 10.93.

EXAMPLE 1451,3-Dihydro-5-Phenyl-3-(RS)-(4'-trifluoromethylbenzoylamino)-2H-1,4-benzodiazepin-2-one

The procedure of Example 137 was carried out using4-trifluoromethylbenzoyl chloride in place of o-chlorobenzoyl chloride.The reaction was chromatographed on silica gel using chloroform as theelution solvent.

TLC: Silica gel 97:3 CHCl₃ :MeOH (CM), R_(f) =0.3.

NMR: Consistent with structure.

HPLC: 99%.

MS: Molecular ion at m/e 423.

Anal. calc'd for C₂₃ H₁₆ F₃ N₃ O₂ : C, 65.24; H, 3.81; N, 9.92; Found:C, 65.14; H, 3.94; N, 9.69.

EXAMPLE 1461,3-Dihydro-3-(RS)-(4'-tert-butylbenzoylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 137 was carried out using 4-tert-butylbenzoylchloride in place of o-chlorobenzoyl chloride. The reaction waschromatographed on silica gel using chloroform as the elution solvent.

TLC: Silica 97:3, CHCl₃ :MeOH, R_(f) =0.35.

NMR: Consistent with structure.

HPLC: 98%.

MS: Molecular ion at m/e 411.

Anal. calc'd for C₂₆ H₂₅ N₃ O₂ 0.14CHCl₃ : C, 73.31; H, 5.92; N, 9.81;Found: C, 73.69; H, 6.07; N, 9.78.

EXAMPLE 1473-(RS)-(3,5-Dichlorobenzoylamino)1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The EDC procedure in Example 126 was carried out using3,5-dichlorobenzoic acid in place of 5-methoxyindole-2-carboxylic acid.The reaction was diluted with chloroform and chromatographed on a silicagel column with chloroform as the elution solvent.

TLC: Silica gel 97:3 CHCl₃ :MeOH (CM), R_(f) =0.5

NMR: Consistent with structure.

HPLC: 96%.

MS: Molecular ion at m/e 423.

Anal. calc'd for C₂₂ H₁₅ Cl₂ N₃ O₂ : C, 62.27; H, 3.56; N, 9.90; Found:C, 62.65; H, 3.67; N, 9.80.

EXAMPLE 1481-3-Dihydro-3-(RS)-(p-Hydroxybenzoylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

The EDC procedure in Example 126 was carried out using p-hydroxybenzoicacid in place of 5-methoxyindole-2-carboxylic acid. The reaction waschromatographed on silica gel with chloroform as the elution solvent.

TLC: Silica gel 97:3 CHCl₃ :MeOH, R_(f) =0.50.

NMR: Consistent with structure.

HPLC: 99%.

MS: Molecular ion at 371.

Anal. calc'd for C₂₂ H₁₇ N₃ O₃ : C, 71.15; H, 4.61; N, 11.31; Found: C,70.05; H, 4.63; H, 11.21.

EXAMPLE 1493-(RS)-(4'-Cyanobenzoylamino)1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure in Example 137 was carried out using 4-cyanobenzoylchloride in place of o-chlorobenzoyl chloride. The reaction waschromatographed on silica gel using chloroform followed by 98:2 CHCl₃:MeOH (CM) as the elution solvents.

TLC: Slica gel 97:3 CM, R_(f) =0.3.

NMR: Consistent with structure.

HPLC: 99.6%.

MS: Molecular ion at m/e=380.

Anal. calc'd for C₂₃ H₁₆ N₄ O₂ 0.41H₂ O: C, 71.24; H, 4.37; N, 14.45;Found: C, 71.53; H, 4.37; N, 14.73.

EXAMPLE 1503(S)-(-)-3-(2-Chlorobenzoylamino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-phenyl-1-methyl-2H-1,4-benzodiazepin-2-one(41.4 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 2-chlorobenzoylchloride (27.3 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution) The combined productfractions were evaporated to dryness in vacuo to give the title compoundwhich was dried in vacuo at 78° C.: (m.p. 100°-118° C.).

TLC: Single spot, R_(f) =0.24, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=403.

[a]_(D) ²⁵ =-90.4° (1.15 mg/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₈ ClN₃ O: C, 68.40; H, 4.49; N, 10.41; Found: C,68.20; H, 4.73; N, 10.07.

EXAMPLE 1513(R)-(+)-3-(2-Chlorobenzoylamino)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(R)-(+)-3-amino-1,3-dihydro-5-phenyl-1-methyl-2H-1,4-benzodiazepin-2-one(41.4 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,and 2-chlorobenzoyl chloride (27.3 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo to give the title compoundwhich was dried in vacuo at 78° C.: (m.p. 102°-120° C.).

TLC: Single spot, R_(f) =0.24, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=403.

[a]_(D) ²⁵ =+95.4° (1.75 mg/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₈ ClN₃ O: C, 68.40; H, 4.49; N, 10.41; Found: C,68.74; H, 4.68; N, 10.16.

EXAMPLE 1521,3-Dihydro-3(RS)-(p-dimethylaminobenzoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out usingp-dimethylaminobenzoyl chloride (28.6 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The citric acid and sodiumbicarbonate washes were omitted. The title compound was crystallizedfrom CH₂ Cl₂ (6 ml)/Et₂ O (5 ml) and dried in vacuo at 90°: (m.p.256°-258° C.).

TLC: Single spot, R_(f) =0.60, silica gel plate, 90:10 1:1 (v:v:v:v) CH₂Cl₂ :MeOH:HOAc:H₂ O.

NMR: The spectrum was consistent with the title structure and verifiedthe presence of H₂ O.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=416.

Anal. calc'd for C₂₄ H₂₁ FN₄ O₂. 0.15H₂ O: C, 68.77; H, 5.12; N, 13.37;Found: C, 68.73; H, 5.16; N, 13.27.

EXAMPLE 1531,3-Dihydro-3(RS)-(3,4-dimethoxybenzoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using 3,4-dimethoxybenzoylchloride (31.3 mg, 0.156 mmole) in place of p-trifluoromethylbenzoylchloride. The title compound was crystallized from CH₂ Cl₂ (1.5 ml)/Et₂O (3 ml) and dried in vacuo at 90°: (m.p. 206°-207.5° C.).

TLC: Single spot, R_(f) =0.64, silica gel plate, 90:10:1:1 (v:v:v:v) CH₂Cl₂ :MeOH:HOAc:H₂ O.

NMR: The spectrum was consistent with the title structure and verifiedthe presence of Et₂ O and CH₂ Cl₂.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=433.

Anal. calc'd for C₂₄ H₂₀ FN₃ O₄. 0.13C₄ H₁₀ O. 0.13CH₂ Cl₂ : C, 65.24;H, 4.79; N, 9.26; Found: C, 65.22; H, 4.55; N, 9.14.

EXAMPLE 1543(S)-(+)-3-(3-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 3-bromobenzoyl chloride (34.2 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The title compound was crystallizedfrom Et₂ O and dried in vacuo at 100° C.: (m.p. 172°-178° C.).

TLC: Single spot, R_(f) =0.66, silica gel plate, 15% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=465.

[a]_(D) ²⁵ =+16.7°(0.0025 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ BrFN₃ O₂ : C, 59.24; H, 3.67; N, 9.01; Found:C, 59.45; H, 3.80; N, 8.97.

EXAMPLE 1551,3-Dihydro-5-phenyl-3(RS)-(3-trifluoromethylthiobenzoylamino)-2H-1,4-benzodiazepin-2-one

3(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (80.0 mg,0.318 mmole), 3-trifluoromethylthiobenzoic acid (70.7 mg, 0.318 mmole),HBT (43.0 mg, 0.318 mmole) and EDC(61.0 mg, 0.318 mmole) were combinedin dry DMF (2 ml) and stirred at room temperature. The pH of the mixturewas adjusted to 9.0-9.5 with triethylamine (64.4 mg, 0.636 mmole) andthe mixture stirred for 10 minutes. The DMF was removed in vacuo, andthe residue was treated with 10% citric acid and extracted with EtOAc.The combined organic fractions were washed with sodium carbonatesolution, dried over Na₂ SO₄, filtered, and evaporated to dryness invacuo. The residue was crystallized from EtOAc to give the titlecompound which was dried in vacuo at 100° C.: (m.p. 230°-232° C.).

TLC: Single spot, R_(f) =0.32, silica gel plate, 15% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=455.

Anal. calc'd for C₂₃ H₁₆ F₃ N₃ O₂ S: C, 60.65; H, 3.54; N, 9.23; Found:C, 60.82; H, 3.51; N, 9.35.

EXAMPLE 1563(S)-(+)-3-(4-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-bromobenzoyl chloride (34.2 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The title compound waschromatographed on silica gel (5% Et₂ O in CH₂ Cl₂ elution) and theproduct fractions evaporated to dryness in vacuo. The title compound wasdried in vacuo at 82° C.: (m.p. 123°-135° C.).

TLC: Single spot, R_(f) =0.46, silica gel plate, 10% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=465.

[a]_(D) ²⁵ =+9.6° (0.0023 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ BrFN₃ O₂ : C, 59.24; H, 3.67; N, 9.01; Found:C, 59.12; H, 3.75; N, 8.77.

EXAMPLE 1573(S)-(+)-3-(4-t-Butylbenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-t-butylbenzoyl chloride (30.7 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (4% Et₂ O in CH₂ Cl₂ elution), and the product fractionsevaporated to dryness in vacuo. The title compound was dred in vacuo at82° C.: (m.p. 184°-190° C.).

TLC: Single spot, R_(f) =0.37, silica gel plate, 5% (v/v Et₂ O in CH₂Cl₂).

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=443.

[a]_(D) ²⁵ =+6.7° (0.0021 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₇ H₂₆ FN₃ O₂ : C, 73.12; H, 5.91; N, 9.48; Found: C,73.03; H, 6.11; N, 9.44.

EXAMPLE 1581,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(pyrrole-2-carbonylamino)-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using pyrrole-2-carbonylchloride (20.2 mg, 0.156 mmole) in place of p-trifluoromethylbenzoylchloride. Without washing, the reaction mixture was chromatographed onsilica gel (225:10:1:1 (v:v:v:v) CH₂ Cl₂ :MeOH:HOAc:H₂ O elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized from EtOAc to give the title compound which was dried invacuo at 82° C.: (m.p. 271°-274° C.).

TLC: Single spot, R_(f) =0.35, silica gel plate, 180:10:1:1 (v/v/v/v)CH₂ Cl₂ :MeOH:HOAc:H₂ O.

NMR: Consistent with structure, verifies presence of 0.25 EtOAc.

HPLC: Greater than 95% pure.

MS: Molecular ion at m/e=362.

Anal. calc'd for C₂₀ H₁₅ FN₄ O₂.0.25C₄ H₁₀ O: C, 65.62; H, 4.46; N,14.58; Found: C, 65.60; H, 4.55; N, 14.53.

EXAMPLE 1593(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(4-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-(dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-iodobenzoyl chloride (41.6 mg, 0.156 mmole in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution) and the product fractionsevaporated to dryness in vacuo. The title compound was dried in vacuo at82° C.: (m.p. 128°-140° C.).

TLC: Single spot, R_(f) =0.51, silica gel plate, 10% (v/v) Et₂ O in CH₂C₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=513.

[a]_(D) ²⁵ =+8.4° (0.0028 g/ml CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ FIN₃ O₂ : C, 53.82; H, 3.34; N, 8.19; Found: C,53.72; H, 3.44; N, 8.00.

EXAMPLE 1601,3-Dihydro-3(RS)-(2-naphthoylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg,0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 2-naphthoyl chloride (29.7 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (15% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from CH₂Cl₂ /EtOAc to give the title compound which was dried in vacuo at 82°C.: (m.p. 293°-294° C.).

TLC: Single spot, R_(f) =0.28, silica gel plate, 15% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=405.

Anal. calc'd for C₂₆ H₁₉ N₃ O₂ : C, 77.02; H, 4.72; N, 10.37; Found: C,76.88; H, 4.85; N, 10.50.

EXAMPLE 1613(S)-(-)-3-(2-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 2-bromobenzoyl chloride (34.2 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to drynss. The residue was crystallized fromEt₂ O to give the title compound which was dried in vacuo at 82° C.:(m.p. 165°-185° C.).

TLC: Single spot, R_(f) =0.38, silica gel plate, 10% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=465.

[a]_(D) ²⁵ =-24.1° (0.0037 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ BrFN₃ O₂ : C, 59.24; H, 3.67; N, 9.01; Found:C, 59.14; H, 3.61; N, 9.06.

EXAMPLE 1623(S)-(+)-3-(4-Cyanobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazeoin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-cyanobenzoyl chloride (25.8 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (8% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo to give the title compoundwhich was dried in vacuo at 82° C.: (m.p. 130°-147° C.).

TLC: Single spot, R_(f) =0.29, silica gel plate, 10% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure, verifies presence of 0.1 Et₂ O.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=412.

[a]_(D) ²⁵ =+13.0° (0.0027 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₄ H₁₇ FN₄ O₂. 0.1C₄ H₁₀ O: C, 69.80; H, 4.32; N,13.34; Found: C, 69.50; H, 4.43; N, 13.44.

EXAMPLE 1631,3-Dihydro-5-phenyl-3(RS)-(4-α-propylbenzoylamino)-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg,0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin- 2-oneand 4-n-propylbenzoyl chloride (28.5 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (15% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from Et₂O to give the title compound which was dried in vacuo at 82° C.: (m.p..158°-162° C.).

TLC: Single spot, R_(f=) 0.24, silica gel plate, 15% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=397.

Anal. calc'd for C₂₅ H₂₃ N₃ O₂ : C, 75.54; H, 5.83; N, 10.57; Found: C,75.16; H, 5.98; N, 10.74.

EXAMPLE 1641,3-Dihydro-5-phenyl-3(RS)-(4-phenylbenzoylamino)-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg,0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-phenylbenzoyl chloride (33.8 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (15% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from Et₂O to give the title compound which was dried in vacuo at 82° C.: (m.p.274°-276° C.).

TLC: Single spot, R_(f) =0.24, silica gel plate, 15% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=431.

Anal. calc'd for C₂₈ H₂₁ N₃ O₂ : C, 77.94; H, 4.91; N, 9.74; Found: C,77.69; H, 5.17; N, 9.84.

EXAMPLE 1651,3-Dihydro-3(RS)-(4-n-pentylbenzoylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg,0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-n-pentylbenzoyl chloride (32.9 mg, 0.156 mmole) in place ofp-trifluorobenzoyl chloride. The product was chromatographed on silicagel (15%, (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from Et₂O to give the title compound which was dried in vacuo at 82° C.: (m.p.203°-205° C.).

TLC: Single spot, R_(f) =0.28, silica gel plate, 15% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=425.

Anal. calc'd for C₂₇ H₂₇ N₃ O₂ : C, 76.21; H, 6.40; N, 9.88; Found: C,76.07; H, 6.53; N, 10.00.

EXAMPLE 1661,3-Dihydro-3(RS)-(1-naphthoylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg,0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 1-naphthoyl chloride (29.7 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (15% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from Et₂O to give the title compound which was dried in vacuo at 65° C.: (m.p.162°-167° C.).

TLC: Single spot, R_(f) =0.22, silica gel plate, 15% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 96% pure.

MS: Molecular ion at m/e=405.

Anal. calc'd for C₂₆ H₁₉ N₃ O₂ : C, 77.02; H, 4.72; N, 10.37; Found: C,77.20; H, 4.91; N, 10.25.

EXAMPLE 1673(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(3-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 3-iodobenzoyl chloride (41.6 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution) The combined productfractions were evaporated to dryness in vacuo to give the title compoundwhich was dried in vacuo at 65° C.: (m.p. 105°-120° C.).

TLC: Single spot, R_(f) =0.34, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR Consistent with structure.

HPLC: Greater than 96% pure. MS: Molecular ion at m/e=513.

[a]_(D) ²⁵ =+13.0° (0.0024 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ FIN₃ O₂ : C, 53.82; H, 3.34; N, 8.19; Found: C,54.10; H, 3.46; N, 8.18.

EXAMPLE 1683(R)-(-)-1,3-Dihydro-5-(2-fluorophenyl)-3-(3-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(R)-(+)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 3-iodobenzoyl chloride (41.6 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo to give the title compoundwhich was dried in vacuo at 65° C.: (m.p. 169°-172° C.).

TLC: Single spot, R_(f) =0.38, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: -Molecular ion at m/e=513.

[a]_(D) ²⁵ =-10.2° (0.0026 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ FIN₃ O₂ : C, 53.82; H, 3.34; N, 8.19; Found: C,54.07; H, 3.42; N, 8.50.

EXAMPLE 1693(R)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(R)-(+)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,and 2-iodobenzoyl chloride (41.6 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution) The combined productfractions were evaporated to dryness in vacuo and crystallized fromether to give the title compound which was dried in vacuo at 65° C.:(m.p. 231°-235° C.).

TLC: Single spot, R_(f) =0.24, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=513.

[a]_(D) ²⁵ +26.1° (0.0028 g/ml, CH₂ Cl₂)

Anal. calc'd for C₂₃ H₁₇ FIN₃ O₂ : C, 53.82; H, 3.34; N, 8.19; Found: C,53.71; H, 3.38; N, 8.14.

EXAMPLE 1703(S)-(-)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(S)-(-)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 2-iodobenzoyl chloride (41.6 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from Et₂O to give the title compound which was dried in vacuo at 65° C.: (m.p.230°-232° C.).

TLC: Single spot, R_(f) =0.24, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=513.

[a]_(D) ²⁵ =25.6° (0.0029 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ FIN₃ O₂ : C, 53.82; H, 3.34; N, 8.19; Found: C,53,62; H, 3.25; N, 8.30.

EXAMPLE 1713(R)-(+)-3-(2-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(R)-(+)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 2-bromobenzoyl chloride (34.2 mg, 0.156 mmole) in place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from Et₂O to give the title compound which was dried in vacuo at 65° C.: (m.p.155°-160° C.).

TLC: Single spot, R_(f) =0.28, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=465.

[a]_(D) ²⁵ =+26.3° (0.0034 g/ml, CH₂ Cl₂)

Anal. calc'd for C₂₃ H₁₇ BrFN₃ O₂ : C, 59,24; H, 3.67; N, 9.01; Found:C, 59.15; H, 3.70; N, 9.12.

EXAMPLE 1723(R)-(+)-3-(2-Chlorobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using3(R)-(+)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one(44.2 mg, 0.156 mmole) in place of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 2-chlorobenzoyl chloride (27.3 mg, 0.156 mmole) in Place ofp-trifluoromethylbenzoyl chloride. The product was chromatographed onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized from CH₂Cl₂ to give the title compound which was dried in vacuo at 65° C.: (m.p.157°-165° C.).

TLC: Single spot, R_(f) =0.25, silica gel plate, 5% (v/v) Et₂ O in CH₂Cl₂.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=421.

[a]_(D) ²⁵ =+16.7° (0.0032 g/ml, CH₂ Cl₂).

Anal. calc'd for C₂₃ H₁₇ ClFN₃ O₂ : C, 65.48; H, 4.06; N, 9.96; Found:C, 65.63; H, 4.10; N, 10.03.

EXAMPLE 1731,3-Dihydro-5-(2-fluorophenyl)-3(RS)-phenylcarbonylamino-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using benzoyl chloride(21.9 mg, 0.156 mmole) in Place of p-trifluoromethylbenzoyl chloride.The title compound was crystallized from ethyl acetate and dried invacuo at 75° C.: (m.p. 243°-244° C.).

TLC: Single spot, R_(f) =0.18, silica gel plate, (chloroform-methanol,1:1 v/v).

NMR: The spectrum was consistent with the title structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=373.

Anal. calc'd for C₂₂ H₁₆ FN₃ O₂ : C, 70.76; H, 4.32; N, 11.25; Found: C,70.63; H, 4.35; N, 11.07.

EXAMPLE 1741,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(2-chlorophenyl)carbonylamino-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using 2-chlorobenzoylchloride (27.3 mg, 0.156 mmole) in place of p-trifluoromethylbenzoylchloride. The title compound was crystallized from ethyl acetate anddried in vacuo at 75° C.: (m.p. 224°-224.5° C.).

TLC: Single spot, R_(f) =0.27, silica gel plate, (chloroform-methanol,97:3 v/v).

NMR: The spectrum was consistent with the title structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=407.

Anal. calc'd for C₂₂ H₁₅ ClFN₃ O₂. 0.1C₄ H₈ O₂ : C, 64.57; H, 3.82; N,10.08; Found: C, 64.30; H, 3.76; N, 9.99.

EXAMPLE 1751,3-Dihydro-5-(2-fluorophenyl)-3(RS)-benzyloxycarbonylamino-2H-1,4-benzodiazepin-2-one

The procedure of Example 134 was carried out using benzyl chloroformate(26.6 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride.The title compound was crystallized from ethyl acetate and dried invacuo at 75° C.: (m.p. 208° C.).

TLC: Single spot, R_(f) =0.37, silica gel plate, (hexane-ethyl acetate,1:1 v/v).

NMR: The spectrum was consistent with the title structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=403.

Anal. calc'd for C₂₃ H₁₈ FN₃ O₃ : C, 68.48; H, 4.50; N, 10.42; Found: C,68.84; H, 4.62; N, 10.49.

EXAMPLE 1761,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-benzyloxycarbonylamino-2H-1,4-benzodiazeoin-2-thione

1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-benzyloxycarbonylamino-2H-1,4-benzodiazepin-2-one(6.5 g, 16.1 mmole) and2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane (4.9 g,12.1 mmole) were combined in 500 ml of toluene and heated at reflux for1.5 hours. The reaction mixture was cooled, diluted to 700 ml with ethylacetate and washed with 10% sodium hydroxide solution (4×50 ml) andbrine. The organic phase was dried (Na₂ SO₄) and concentrated underreduced pressure to yield 12 g of crude product. Trituration with ethylacetate gave 4.0 g of the analytical product as a yellow powder.Chromatography of the mother liquors on silica gel (hexane-ethyl acetateelution, 1:1 v/v) afforded an additional 2.2 g of pure product: m.p.190°-191° C.

NMR (CDCl₃) Confirmed structure of the title compound.

MS (14 ev): 419 (M⁺), 311, 284, 256, 243, 224.

Anal. calc'd for C₂₃ H₁₈ FN₃ O₂ S: N, 10.02; C, 65.86; H, 4.33; Found:N, 9 79; C, 65.59; H, 4.44.

EXAMPLE 1771-(4-Chlorophenyl)carbonyl-1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(4-chlorophenyl)carbonylamino-2H-1,4-benzodiazepin-2-one

To a solution of1,3-dihydro-5-(2-fluorophenyl)-3-amino-2H-1,4-benzodiazepin-2-one (400mg, 1.49 mmole) in 25 ml of methylene chloride was added p-chlorobenzoylchloride (380 μl, 3.0 mmole). Triethylamine was added to bring the pH ofthe reaction mixture to approximately 6 (moist pH paper) followed by4-dimethylamino pyridine (183 mg, 1.5 mmole). After stirring at roomtemperature overnight the reaction mixture was diluted with methylenechloride to 200 ml and washed in succession with 10% citric acidsolution (3×50 ml), saturated sodium bicarbonate solution, and brine.The organic extracts were dried (MgSO₄) and concentrated to give 890 mgof crude product. Silica gel chromatography (hexane-ethyl acetate, 1:1v/v) afforded the analytical product: m.p. 190°-191° C. TLC: Singlespot, R_(f) =0.70, silica gel (hexane-ethyl acetate, 1:1 v/v).

NMR: The spectrum is consistent with the title structure.

HPLC: Greater than 97% pure.

MS: Molecular ion m/e=546.

Anal. calc'd for C₂₉ H₁₈ Cl₂ FN₃ O₃ : N, 7.69; C, 63.74; H, 3.32; Found:N, 7.58; C, 63.88; H, 3.46.

EXAMPLE 1781-(4-Chlorophenyl)carbonyl-1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(4-chlorophenyl)carbonyloxy-2H-1,4-benzodiazepin-2-one

A suspension of1,3-dihydro-5-(2-fluorophenyl)-3-hydroxy-2H-1,4-benzodiazepin-2-one (610mg, 2.25 mmole) in 25 ml of methylene chloride was treated with4-chlorobenzoyl chloride (0.314 ml, 2.48 mmole) at room temperature.4-Dimethylaminopyridine (303 mg, 2.48 mmole) was added and withinminutes the reaction mixture became homogeneous. The reaction mixturewas protected from moisture and stirred at room temperature overnight.An additional equivalent each of 4-chlorobenzoyl chloride and4-dimethylaminopyridine were added and stirring was continued for 8hours at 40°-45° C. The reaction mixture was diluted to 150 ml withmethylene chloride and washed in succession with 10% citric acidsolution (3×50 ml), saturated sodium bicarbonate solution (3×50 ml) andbrine (50 ml). Rotoevaporation of the dried (MgSO₄) organic phase gave afoam which on trituration with ether afforded a beige solid.Recrystallization from ethyl acetate afforded 612 mg of the titlecompound as a white powder in analytical purity: m.p. 198°-199° C.

NMR (DMSO-d₆): The spectrum is consistent with the title structure.

MS (14 ev): 547 (M⁺), 407, 379, 374, 363, 224, 156.

Anal. calc'd for C₂₉ H₁₇ Cl₂ FN₂ O₄ : N, 5.11; C, 63.63; H, 3.13; Found:N, 5.03; C, 63.68; H, 3.08.

EXAMPLE 1791,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(4-chlorobenzoyl)oxy-2H-1,4-benzodiazepin-2-one

A suspension of1,3-dihydro-5-(2-fluorophenyl)-3-hydroxy-2H-1,4-benzodiazepin-2-one (610mg, 2.25 mmole) in 25 ml of methylene chloride was treated with4-chlorobenzoyl chloride (0.314 ml, 2.48 mmole) at room temperature.4-Dimethylaminopyridine (303 mg, 2.48 mmole) was added and withinminutes the reaction mixture became homogeneous. The reaction mixturewas protected from moisture and stirred at room temperature overnight.An additional equivalent each of 4-chlorobenzoyl chloride and4-dimethylaminopyridine were added and stirring was continued for 8hours at 40°-45° C. The reaction mixture was diluted to 150 ml withmethylene chloride and washed in succession with 10% citric acidsolution (3×50 ml), saturated sodium bicarbonate solution (3×50 ml) andbrine (50 ml). Rotoevaporation of the dried (MgSO₄) organic phase gave afoam which on trituration with ether afforded a beige solid. The motherliquors were concentrated and the residue chromatographed on silica gel(hexane-ethyl acetate, 1:1 v/v) to give the title compound.

NMR (CDCl₃): The spectrum is consistent with the title structure.

Anal. calc'd for C₂₂ H₁₄ ClFN₂ O₃ : N, 6.85; C, 64.63; H, 3.45; Found:N, 6.68; C, 64.64; H, 3.60.

EXAMPLE 1801,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(4-chlorophenyl)carbonylamino-2H-1,4-benzodiazepin-2-thione

A mixture of1,3-dihydro-5-(2-fluorophenyl)-3-(RS)-amino-2H-1,4-benzodiazepin-2-thione(200 mg, 0.70 mmole), 4-chlorobenzoic acid (120 mg, 0.77 mmole) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (150 mg,0.77 mmole) were combined in 2 ml of dry N,N-dimethylformamide at roomtemperature. The pH of the homogeneous reaction mixture was thenadjusted to 8 with triethylamine. The reaction mixture was protectedfrom moisture and stirred at room temperature overnight (about 90%complete after 1 hour). The solvent was removed under reduced pressureand the residue dissolved in 100 ml of ethyl acetate. The organic phasewas then washed in succession with 10% citric acid solution (2×20 ml),saturated sodium bicarbonate solution (20 ml), and brine. The dried(MgSO₄) organic phase was rotoevaporated to dryness to yield 300 mg ofcrude Product. Preparative thick layer chromatography on SiO₂(hexane-ethyl acetate, 2:1) gave the analytical sample as a solvate:m.p. 156°-158° C.

NMR (DMSO-d₆): Confirmed structure of the title compound.

MS (14 ev): 423 (M⁺), 391, 284, 268, 236, 139.

Anal. calc'd for C₂₂ H₁₅ ClFN₃ OS. 0.10C₄ H₈ O₂ : N, 9.71; C, 62.17; H,3.68; Found: N, 9.39; C, 62.45; H, 4.01.

EXAMPLE 181 1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indole)carbonylamino-2H-1,4-benzodiazepin-2-thione

A mixture of1,3-dihydro-5-(2-fluorophenyl)-3-(RS)-amino-2H-1,4-benzodiazepin-2-thione(400 mg, 1.40 mmole), indole-2-carboxylic acid (248 mg, 1.54 mmole) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (295 mg,1.54 mmole) were combined in 10 ml of dry N,N-dimethylformamide at roomtemperature. The pH of the homogeneous reaction mixture was thenadjusted to 8 with triethylamine. The reaction mixture was protectedfrom moisture and stirred at room temperature overnight (about 50%complete after 1 hour). The solvent was removed under reduced pressureand the residue dissolved in 200 ml of ethyl acetate. The organic phasewas then washed in succession with 10% citric acid solution (2×25 ml),saturated sodium bicarbonate solution (25 ml), and brine. The dried(MgSO₄) organic phase was rotoevaporated to dryness to yield 1.4 g ofcrude product. Preparative thick layer chromatography on SiO₂(hexane-ethyl acetate, 1:1) gave the analytical sample as a beigepowder: m.p. 209°-211° C.

NMR (CDCl₃): Confirmed structure of the title compound.

MS (14 ev): 428 (M⁺), 396, 394, 296, 293, 252, 249.

Anal. calc'd for C₂₄ H₁₇ FN₄ OS.0.15C₄ H₈ O₂ : N, 12.69; C, 66.89; H,4.15; Found: N, 12.92; C, 6.69; H, 3.90.

EXAMPLE 1821,3-Dihydro-3(RS)-(4-chlorophenyl)aminocarbonylamino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

To a solution of 85 mg (0.315 mmole) of1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in8 ml of dry tetrahydrofuran was added 4-chlorophenylisocyanate (40 μl,0.315 mmole) at room temperature. Within 15 minutes a flocculant, whiteprecipitate formed. Stirring was continued for 8 hours more and thereaction mixture was filtered. The collected solids were washed with hotmethanol and dried in vacuo to give the analytical product: m.p. 278° C.NMR (DMSO-d₆): Confirms structure assignment of product.

Anal. calc'd for C₂₂ H₁₆ ClFN₄ O₂ : N, 13.25; C, 62.48; H, 3.81; Found:N, 13.09; C, 62.33; H, 3.86.

EXAMPLE 1831,3-Dihydro-1-methyl-3-oximino-5-phenyl(-2H-1,4-benzodiazeoin-2-one

To a suspension of potassium tert-butoxide (24.9 g, 222 mmole) in 600 mlof dry tetrahydrofuran was added 200 ml of dry tert-butylalcohol at -20°C. under nitrogen. To this solution was then added via, addition funnel1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (25 g, 99.9mmole) in 260 ml of tetrahydrofuran. The resulting wine colored solutionwas stirred for 2 hours at -20° C. and treated with 17.4 ml (130 mmole)of isoamyl nitrite. The reaction mixture was warmed to 0° C. over 15minutes and quenched with the addition of 60 ml of cold water and 20 mlof glacial acetic acid. All solvents were removed under reduced pressureand the residue was partitioned between ethyl acetate (600 ml) and brine(100 ml). The phases were separated and the organic extracts were dried(Na₂ SO₄) and concentrated. The resulting semi-solid was triturated withether to give 21 g of off-white solid., m.p. 234°-235° C.; R_(f) =0.15(ethylacetate-hexane, 1:1); R_(f) =0.28 chloroform-ethanol, 95:5);

ir(KBr, partial): 3300, 1650, 1595, 1320, 1205, 1030, 975 cm⁻¹.

MS (14 ev.): 279 (M⁺), 262, 249, 236, 222.

¹ HNMR (CDCl₃): 3.5 (3H, CH₃ -N), confirms structure assignment.

Elemental Analysis Calc'd for C₁₆ H₁₃ N₃ O₂ : C, 4.69; H, 68.81; N,15.04. Found: C, 4.62; H, 68.67; N, 15.08.

EXAMPLE 1843(R,S)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

A solution of 150 ml of methanol containing 5 g (17.9 mmole) of1,3-dihydro-1-methyl-3-oximino-5-phenyl-1,4-benzodiazepin-2-one wastreated with a slurry of active Raney-nickel catalyst¹ (10 g wetweight). The resulting suspension was hydrogenated on a Parr apparatusat 60 psi and 23° C. for 30 hours. The catalyst was removed byfiltration and the filtrate was concentrated to afford the titlecompound in 95% yield.

R_(f) =0.23 (chloroform-ethanol, 95:5), R_(f) =0.23(chloroform-methanol-acetic acid-water, 90:10:1:1)

¹ HNMR (CDCl₃): spectrum confirms structure assignment.

EXAMPLE 1854-Cyano-N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide

The procedure of Example 134 was carried out employing equivalentamounts of 1,3-dihydro-3-(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-cyanobenzoylchloride. The product was purified by chromatographyon silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized to givethe title compound which was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=388.

Anal. Calc'd for C₂₃ H₁₆ N₄ O₂.0.41H₂ O: C, 71.24; H, 4.37; N, 14.73.Found: C, 71.53; H, 4.37; N, 14.73.

EXAMPLE 186(S)-α-Amino-N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzenepropanamide

A solution of 1.55 gm (3.11 mmol)α-t-butyloxycarbonylamino-N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzenepropanamidein 10 ml EtoAc was cooled in an ice bath, saturated with HCl(g) andstirred 10 minutes. The solvent was removed in vacuo and the residuetreated with saturated Na₂ CO₃ and extracted (3×EtOAc). The organicswere combined, washed 1×H₂ O, 1×brine, dried over Na filtered and thesolvent removed in vacuo. The residue was flash chromatographed onsilica gel (90/10/1/1 of CH₂ Cl₂ /MeOH/H₂ O/HOAc) and a clean higherR_(f) component was isolated. After conversion to the free base (Na₂ CO₃(aq)/EtOAc) the title compound crystallized from EtOAc: mp. 208°-210° C.

NMR: Confirms structure assignment of product and verifies presence ofH₂ O.

HPLC: Greater than 98.9% pure.

MS: Molecular ion at m/e=398 (free base).

Anal. Calc'd for C₂₄ H₂₂ N₄ O₂.0.1 H₂ O: C, 72.02; H, 5.59; N, 14.00.Found: C, 72.01; H, 5.50; N, 14.01.

EXAMPLE 1873(S)-(2-Indolecarbonyl)amino-1,3-dihydro-5-phenyl-2H-1,4,-benzodiazepin-2-one

Equimolar amounts of3(S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one,indole-2-carbonyl chloride and triethylamine were mixed in CH₂ Cl₂ atroom temperature and stirred 10 minutes. Flash chromatography of thereaction solution on silica gel (25% Et₂ O in CH₂ Cl₂ provided the titlecompound as a white solid after removal of the solvent: m.p. 188°-95° C.

NMR: Confirms structure assignment of product and verifies presence ofCH₂ Cl₂.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=394 (free base).

Anal Calc'd for C₂₄ H₁₈ N₄ O₂.0.06 CH₂ Cl₂ : C, 72.33; H, 4.57; N,14.03. Found: C, 72.32; H, 4.47; N, 14.08.

[a]_(D) ²⁵ =-88.1° (conc. 1.6 mg/ml CH₂ Cl₂).

EXAMPLE 1883-(2'-Chlorobenzoylamino)-1-ethoxycarbonylmethyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine-2-one

The procedure of Example 4 was employed using equimolar amounts ofethylbromoacetate and1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-3-(RS)-(2-chlorophenylcarbonyl)amino-2H-1,4-benzodiazepin-2-one.The chromatographed product was dried in vacuo at room temperature.

NMR: Consistent with structure assignment.

HPLC: Greater than 95% pure.

MS: Molecular ion at m/e=494.

Anal. Calc'd for C₂₆ H₂₁ ClFN₃ O₄.0.4H₂ O: C, 62.31; H, 4.39; N, 8.39.Found: C, 62.39; H, 4.39; N, 8.36.

EXAMPLE 189(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-methylpropanamide

Equimolar amounts of3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,isobutyryl chloride, and triethylamine were mixed in CH₂ Cl₂ at roomtemperature and stirred 10 minutes. Flash chromatography of the reactionsolution on silica gel (10% Et₂ O in CH₂ Cl₂) provided the titlecompound as a white foam upon removal of the solvent: m.p. 87°-107° C.

NMR: Confirms structure assignment of product and verifies presence ofH₂ O.

HPLC: Greater than 99.0% pure.

MS: Molecular ion at m/e=335 (free base).

Anal. Calc'd for C₂₀ H₂₁ N₃ O₂.0.2 H₂ O: C, 70.86; H, 6.36; N, 12.40.Found: C, 70.71; H, 6.40; N, 12.40.

[α]_(D) ²⁵ =-96.8° (conc.=2.2 mg/ml CH₂ Cl₂).

EXAMPLE 190(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-methylbutanamide

Equimolar amounts of3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,isovaleryl chloride and triethylamine were mixed in CH₂ Cl₂ at roomtemperature and stirred 10 minutes. Flash chromatography of the reactionsolution on silica gel (10% Et₂ O in CH₂ Cl₂) provided the titlecompound as a white foam from Et₂ O: m.p. 83°-102° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99.0% pure.

MS: Molecular ion at m/e=349.

Anal. Calc'd for C₂₁ H₂₃ N₃ O₂ : C, 72.18; H, 6.64; N, 12.03. Found: C,71.92; H, 6.88; N, 12.05.

[α]_(D) ²⁵ =-94.2° (conc.=3.1 mg/ml CH₂ Cl₂).

EXAMPLE 191(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-cyclohexanecarboxamide

Equimolar amounts of3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,cyclohexane carboxylic acid chloride and triethylamine were mixed in CH₂Cl₂ at room temperature and stirred 10 minutes. Flash chromatography ofthe reaction solution on silica gel (10% Et₂ O in CH₂ Cl₂) provided thetitle compound as a white solid after removal of the solvent: m.p.212°-214° C.

NMR: Confirms structure assignment of product and verifies presence ofH₂ O.

HPLC: Greater than 98.9% pure.

MS: Molecular ion at m/e=375 (free base).

Anal. Calc'd for C₂₃ H₂₅ N₃ O₂.0.25H₂ O: C, 72.70; H, 6.76; N, 11.06.Found: C, 72.73; H, 6.86; N, 11.25.

[α]_(D) ²⁵ =-89.7° (conc.=3.2 mg/ml)

EXAMPLE 192(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazeoin-3-yl)-3-phenyl-2-propenamide

Equimolar amounts of3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,cinnamoyl chloride, and triethylamine were mixed in CH₂ Cl₂ at roomtemperature and stirred 10 minutes. Flash chromatography of the reactionsolution on silica gel (10% Et₂ O in CH₂ Cl₂) provided the titlecompound as a white solid after removal of the solvent: m.p. 126°-140°C.

NMR: Confirms structure assignment of product and verifies presence ofH₂ O.

HPLC: Greater than 94.6% pure.

MS: Molecular ion at 395 (Free base).

Anal. Calc'd for C₂₅ H₂₁ N₃ O₂.0.25H₂ O: C, 75.07; H, 5.42; N, 10.51.Found: C, 75.02; H, 5.45; N, 10.39.

[α]_(D) ²⁵ =-80.6° (conc.=2.13 mg/ml CH₂ Cl₂).

EXAMPLE 193(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2,2-dimethylpropanamide

Equimolar amounts of3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,trimethylacetylchloride and triethylamine were mixed in CH₂ Cl₂ at roomtemperature and stirred 10 minutes. Flash chromatography of the reactionsolution on silica gel (10% Et₂ O in CH₂ Cl₂) provided the titlecompound as a white foam after removal of the solvent: m.p. 85°-94° C.

NMR: Confirms structure assignment of product and verifies presence oftrimethylacetic acid.

HPLC: Greater than 98.9% pure.

MS: Molecular ion at m/e=349 (free base).

Anal. Calc'd for C₂₁ H₂₃ N₃ O₂.0.15C₅ H₁₀ O₂ : C, 71.62; H, 6.77; N,11.52. Found: C, 71.57; H, 6.85; N, 11.48.

[α]_(D) ²⁵ =-97.1° (conc.=3.15 mg/ml CH₂ Cl₂).

EXAMPLE 1943-((((4-Chlorophenyl)amino)carbonyl)amino)-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-aceticacid ethyl ester

Equimolar amounts of3-(RS)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 253°-254° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=509.

Anal. Calc'd for C₂₆ H₂₂ ClFN₄ O₄ : C, 61.36; H, 4.36; N, 11.01. Found:C, 61.33; H, 4.44; N, 10.90.

EXAMPLE 1955-(2-Fluorophenyl)-2,3-dihydro-2-oxo-((((1-phenylethyl)amino)carbonyl)amino)-1H-1,4-benzodiazepine-1-aceticacid ethyl ester

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one-and(+)-α-methylphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to givethe analyticalproduct as a 1:1 mixture of diastereomers: m.p. 160°-162° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=503.

Anal. Calc'd for C₂₈ H₂₇ FN₄ O₄ : C, 66.92; H, 5.42; N, 11.15. Found: C,66.57; H, 5.59; N, 10.82.

EXAMPLE 1963-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-2-amino-4-chlorobenzamide

3-(R,S)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(150 mg, 0.56 mmol) and 2-amino-4-chlorobenzoic acid were coupledaccording to the mixed anhydride method. Thus, the benzoic acid analoguewas dissolved in 10 ml of 10:1 v/v methylene chloride-DMF at -5° C. andtreated with N-methylmorpholine (75 μl, 0.68 mmol) andi-butylchloroformate (90 μl, 0.68 mmol). After 15 minutes, theaminobenzodiazepine was added and stirring was continued at 0° C. for 1hour, then at 23° for 12 hours. Extractive work-up afforded the crudeproduct which was chromatographed on silica gel using hexane-ethylacetate (2:1 v/v). The analytical product was a foam which melted at146° C.

NMR: Confirms structure assignment.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=419.

Anal. Calc.d for C₂₃ H₁₉ ClN₄ O₂.H₂ O: C, 63.22; H, 4.84; N, 12.82.Found: C, 63.49; H, 4.49; N, 12.79

EXAMPLE 197N-(4-Chlorphenyl)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxamide

Freshly distilled THF (3ml) was treated with 0.167 ml (1.20 mmol)diisopropylamine and cooled to -75° C. under a N₂ atmosphere. n-Butyllithium in hexane (1.20 mmol, 0.774 ml of 1.55 M) was added, thesolution stirred 5 minutes and then allowed to warm to room temperature.The solution was recooled to -75° C. and 150 mg (0.60 mmol) of1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one was added in 25mg increments as a solid. The red suspension was stirred 5 minutes andthen warmed to room temperature. The solution was recooled to -75° C.,76.8 ml (0.60 mmol) of p-chlorophenylisocyanate was added, stirred 5minutes and then warmed to room temperature. After stirring 1 hour,brine was added and the mixture was extracted (3x EtOAc). The organicswere combined, washed (2x H₂ O, 1x brine), dried over Na₂ SO₄, filteredand the solvent was removed in vacuo. The residue was flashchromatographed on silica gel (5% Et₂ O in CH₂ Cl₂) to give the titlecompound which was crystallized from ether: m.p. 159°-165° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99.9% pure.

MS: Molecular ion at m/e=403

Anal. Calc'd for C₂₃ H₁₈ ClN₃ O₂ : C, 68.40; H, 4.49; N, 10.41. Found:C, 68.33; H, 4.61; N, 10.35

EXAMPLE 198(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-cyclohexanecarboxamide

The procedure of Example 134 was carried out using equivalent amounts of3(R)-(+)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand cyclohexane carboxylic acid chloride. The product was puridied bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C. m.p.212°-214° C.

NMR: Consistent with structure.

HPLC: Greater than 97% Pure.

MS: Molecular ion at m/e=375

Anal. Calc'd for C₂₃ H₂₅ N₃ O₂ : C, 73.57; H, 6.71; N, 11.19. Found: C,73.22; H, 6.81; N, 11.16.

EXAMPLE 1993-((2,3-Dihydro-1H-indol-3-yl)methyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 9 was followed in which3(R)-[(1H-indol-3-yl)methyl]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-onewas reduced to give the tile compound. The analytical sample wasobtained after silica gel chromatography using hexane-ethyl acetate.

NMR: Consistent with structure.

HPLC: Greater than 95% pure.

MS: Molecular ion at m/e=367

Anal. Calc'd for C₂₄ H₂₁ N₃ O: C, 78.45; H, 5.76; N, 11.44. Found: C,78.84; H, 5.75; N, 11.18.

EXAMPLE 200 1,3-Dihydro-1-methyl-3-((1-methyl-1H-indol-3-yl)methyl)-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was employed using equimolar amounts ofiodomethane and1,3-dihydro-5-phenyl-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2one.The chromatographed product was dried in vacuo at room temperature as afoam.

NMR: Consistent with structure assignment.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=393.

Anal. Calc'd for C₂₆ H₂₃ N₃ O: C, 79.36; H, 5.89; N, 10.68. Found: C,79.68; H, 6.02; N, 10.57.

EXAMPLE 201(S)-N-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-pentylbenzamide

The procedure of Example 134 was carried out using equivalent amounts of3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-n-pentylbehzoylchloride. The product was purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fracions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C.

[α]_(D) ²⁵ =-82° (conc.=3 mg/ml CH₂ Cl₂).

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=440.

Anal. Calc'd for C₂₈ H₂₉ N₃ O₂ : C, 76.51; H, 6.65; , 9.56. Found: C,76.34; H, 6.91; N, 9.21.

EXAMPLE 2023-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-aceticacid

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-carboxy-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 178°-180° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=463.

Anal. Calc'd for C₂₄ H₁₉ ClN₄ O₄.1/4H₂ O: C, 61.67; H, 4.21; N, 11.99.Found: C, 61.61; H, 4.29; N, 11.79.

EXAMPLE 203(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide

The procedure of Example 134 was carried out using equivalent amounts of3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-trifluoromethylbenzoylchloride. The product was purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C.: m.p.125°-127° C.;

[α]_(D) ²⁵ =-65° (conc.=3 mg/ml CH₂ Cl₂).

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=437.

Anal. Calc'd for C₂₄ H₁₈ F₃ N₃ O₂.0.25C₆ H₁₄ : C, 66.73; H, 4.72; N,9.15. Found: C, 66.95; H, 4.67; N, 9.18.

EXAMPLE 2043-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-aceticacid ethyl ester

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 228°-229° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=491.

Anal. Calc'd for C₂₆ H₂₃ ClN₄ O₄ : C, 63.61; H, 4.72; N, 11.41. Found:C, 63.54; H, 4.88; N, 11.08.

EXAMPLE 2055-(2-Fluorophenyl)-2,5-dihydro-3-((((1-methylethyl)amino)carbonyl)amino)-2-oxo-1H-1,4-benzodiazepine-1-aceticacid ethyl ester

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand isoproplylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 155°-157° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=449.

Anal. Calc'd for C₂₃ H₂₅ FN₄ O₄.1/2H₂ O: C, 61.45; H, 5.83; N, 12.46.Found: C, 61.18; H, 5.52; N, 12.37.

EXAMPLE 206(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-pentylbenzamide

The procedure of Example 134 was carried out using equivalent amounts of3(R)-(+)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-n-pentylbenzoylchloride. The product was purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo and driedat 65° C.

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=440.

Anal. Calc'd for C₂₈ H₂₉ N₃ O₂.1/4H₂ O: C, 75.73; H, 6.69; N, 9.46.Found: C, 75.69; H, 6.85; N, 9.45.

EXAMPLE 207(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide

The procedure of Example 134 was carried out using equivalent amounts of3(R)-(+)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-trifluoromethylbenzoylchloride. The product was purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo and driedat 65° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=437.

Anal. Calc'd for C₂₄ H₁₈ F₃ N₃ O₂.1/4C₆ H₁₄ : C, 66.95; H, 4.67; N,9.18. Found: C, 66.92; H, 4.57; N, 9.54.

EXAMPLE 2083-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-aceticacid phenylmethyl ester

Equimolar amounts of3(RS)-amino-1,3-dihydro-1-phenylmethyloxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 220°-222° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=553.

Anal. Calc'd for C₃₁ H₂₅ ClN₄ O₄.0.3H₂ O: C, 66.67; H, 4.62; N, 10.03.Found: C, 66.52; H, 4.42; N, 9.87.

EXAMPLE 2092,3-Dihydro-2-oxo-5-phenyl-3-(((phenylmethoxy)carbonyl)amino)-1H-1,4-benzodiazepine-1-aceticacid ethyl ester

The procedure of Example 4 was employed using equimolar amounts ofethylbromoacetate and1,3-dihydro-3(R,S)-(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one.The chromatographed product (ethyl acetate-hexane) was dried in vacuo atroom temperature over P₂ O₅ : m.p. 65°-66° C.

NMR: Consistent with structure assignment and shows

approximately 10% of the 3,4-double bond isomer.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=472.

Anal. Calc'd for C₂₇ H₂₅ N₃ O₅ : C, 68.78; H, 5.34; N, 8.91. Found: C,68.85; H, 5.55; N, 8.60.

EXAMPLE 210(R)-1,3-Dihydro-3-(1H-indol-3-ylmethyl)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 4 was employed using equimolar amounts ofiodomethane and1,3-dihydro-5-phenyl-3(R)-(3'-indolyl)methyl-2H-1,4-benzodiazepin-2-one.The chromatographed product was dried in vacuo at room temperature as afoam.

NMR: Consistent with structure assignment.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=379.

Anal. Calc'd for C₂₅ H₂₁ N₃ O: C, 79.13; H, 5.58; N, 11.08. Found: C,78.99; H, 5.60; N, 11.03.

EXAMPLE 2113-((2,3-Dihydro-1-methyl-1H-indol-3-yl)methyl)-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

The procedure of Example 9 was followed in which1-methyl-3(R)-[(N-methyl-1H-indol-3-yl)methyl]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-onewas reduced to give the title compound. The analytical sample wasobtained after silica gel chromatography using methylene chloride -ethyl ether (2%).

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=395.

Anal. Calc'd for C₂₆ H₂₅ N₃ O: C, 78.96; H, 6.37; N, 10.63. Found: C,78.45; H, 6.36; N, 10.46.

EXAMPLE 212(2,3-Dihydro-2-oxo-1-(2-oxo-2-((phenylmethyl)amino)ethyl)-5-phenyl-1H-1,4-benzodiazepin-3-yl)-carbamicacid phenylmethyl ester

The procedure of Example 134 was carried out using equivalent amounts of1,3-dihydro-1-chlorocarbonylmethyl-3-(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-oneand aniline. The product was purified by chromatography on silica gel(hexane-ethyl acetate elution). The combined product fractions wereevaporated to dryness in vacuo and crystallized to give the titlecompound which was dried at 65° C.: m.p. 204°-205° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=533.

Anal. Calc'd for C₃₂ H₂₈ N₄ O₄ : C, 72.16; H, 5.30; N, 10.52. Found: C,72.14; H, 5.51; N, 10.73.

EXAMPLE 213{2,3-Dihydro-2-oxo-1-[2-oxo-2-(butylamino)ethyl]-5-phenyl-1H-1,4-benzodiazepin-3-yl}-carbamicacid phenylmethyl ester

The procedure of Example 134 was carried out using equivalent amounts of1,3-dihydro-1-chlorocarbonylmethyl-3-(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-oneand n-butylamine. The product was purified by chromatography on silicagel (hexane-ethyl acetate elution). The combined product fractions wereevaporated to dryness in vacuo and crystallized to give the titlecompound which was dried at 65° C.: m.p. 127°-129° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=499.

Anal. Calc'd for C₂₉ H₃₀ N₄ O₄.0.2H₂ O: C, 69.36; H, 6.10; N, 11.16.Found: C, 69.31; H, 5.89; N, 11.24.

EXAMPLE 2145-(2-Fluorophenyl)-2,3-dihydro-3-((1H-indol-2-ylcarbonyl)amino)-2-oxo-1H-1,4-benzodiazepine-1-aceticacid ethyl ester

The procedure of Example 4 was employed using equimolar amounts ofethylbromoacetate and1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonyl)amino-2H-1,4-benzodiazepin-2-one.The chromatographed product was dried in vacuo at room temperature, andtriturated with ether.

NMR: Consistent with structure assignment and confirms ether solvate.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=498.

Anal. Calc'd for C₂₈ H₂₃ N₄ O₄.0.15C₄ H₁₀ O: C, 67.40; H, 4.85; N,11.00. Found: C, 67.48; H, 5.00; N, 11.23.

EXAMPLE 215(1(2-Ethylamino)-2-oxoethyl)-2,3-dihydro-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-carbamicacid phenylmethyl ester

The products of Example 134 was carried out using equivalent amounts of1,3-dihydro-1-chlorocarbonylmethyl-3(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-oneand ethylamine. The product was purified by chromatography on silica gel(hexane-ethyl acetate elution). The combined product fractions wereevaporated to dryness in vacuo and crystallized to give the titlecompound which was dried at 65°: m.p. 149° C.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=471.

Anal. Calc'd for C₂₇ H₂₆ N₄ O₄ : C, 68.92; H, 5.57; N, 11.91. Found: C,68.92; H, 5.62; N, 12.17.

EXAMPLE 2164-Bromo-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide

The procedure of Example 134 was carried out employing equivalentamounts of1,3-dihydro-1-methyl-3(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and4-bromobenzoyl chloride. The product was purified by chromatography onsilica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized to givethe title compound which was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=448.

Anal. Calc'd for C₂₃ H₁₈ BrN₃ O₂ : C, 61.62; H, 4.05; N, 9.37. Found: C,61.77; H, 3.96; N, 9.12.

EXAMPLE 217N-(4-Chlorophenyl-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of1,3-dihydro-1-methyl-3(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and4-chlorophenyl isocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=419.

Anal. Calc'd for C₂₃ H₁₉ ClN₄ O₂ : C, 65.94; H, 4.52; N, 13.38. Found:C, 65.57; H, 4.76; N, 13.50.

EXAMPLE 218N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide

The procedure of Example 134 was carried out using equivalent amounts of3(R,S)-3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-trifluoromethylbenzoylchloride. The product was purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo to givethe title compound which was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=455.

Anal. Calc'd for C₂₄ H₁₇ F₄ N₃ O₂ : C, 63.30; H, 3.76; N, 9.23. Found:C, 63.48; H, 3.71; N, 9.22.

EXAMPLE 219(S)-N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide

The procedure of Example 134 was carried out using equivalent amounts of3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-trifluoromethylbenzoylchloride. The product was purified bychromatography on siFica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo to givethe title compound which was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=455.

Anal. Calc'd for C₂₄ H₁₇ F₄ N₃ O₂ : C, 63.30; H, 3.76; N, 9.23. Found:C, 63.25; H, 3.87; N, 8.99.

EXAMPLE 2203-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-N-(phenylmethyl,-1H-1,4-benzodiazepine-1-acetamide

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-phenylmethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 260°-262° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=552.

Anal. Calc'd for C₃₁ H₂₆ ClN₅ O₃ : C, 67.45; H, 4.75; N, 12.69. Found:C, 67.30; H, 4.58; N, 12.63.

EXAMPLE 2213-((((4-Chlorophenyl)amino)carbonyl)amino)-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-diethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 284°-285° C.

NMR: Confirms structure with assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=518.

Anal. Calc'd for C₂₈ H₂₈ ClN₅ O₃ : C, 64.92; H, 5.48; N, 13.52. Found:C, 64.88; H, 5.26; N, 13.54.

EXAMPLE 222(1-(2-Diethylamino)-2-oxoethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)phenylmethyl ester

The procedure of Example 134 was carried out using equivalent amounts of1,3-dihydro-1-chlorocarbonylmethyl-3-(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-oneand diethylamine. The product was purified by chromatography on silicagel (hexane-ethyl acetate elution). The combined product fractions wereevaporated to dryness in vacuo to give the title compound which wasdried at 65° C.: m.p. 153°-154° C.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=499.

Anal. Calc'd for C₂₉ H₃₀ N₄ O₄.1/2H₂ O: C, 68.62; H, 6.15; N, 11.04.Found: C, 68.76; H, 5.94; N, 10.88.

EXAMPLE 223N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-pentylbenzamide

The procedure of Example 134 was carried out using equivalent amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-n-pentylbenzoyl chloride. The product was purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution) Thecombined product fractions were evaporated to dryness in vacuo to givethe title compound which was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e458.

Anal. Calc'd for C₂₈ H₂₈ FN₃ O₂.1/4H₂ O: C, 72.94; H, 6.01; N, 9.11.Found: C, 73.08; H, 6.37; N, 9.43.

EXAMPLE 2243-((((4-Chlorophenyl)amino)carbonyl)amino)-N-ethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-ethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 293° C. (d).

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=490.

Anal. Calc'd for C₂₆ H₂₄ ClN₅ O₃ : C, 63.73; H, 4.94; N, 14.29. Found:C, 63.37; H, 5.15; N, 14.22.

EXAMPLE 225(1-((3-((2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)methyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-3-methylbutyl)-carbamicacid-1,1-dimethylethyl ester

The procedure of Example 21 was carried out using the same reagents andamounts except that1,3-dihydro-5-phenyl-3(R)-3'-α,β-indolenyl)methyl-2H-1,4-benzodiazepin-2-onewas substituted for the 5-(2-fluorophenyl) analog. The purified product(silica gel chromatography) was dried at 65° C. in vacuo.

NMR: Structure assignment is consistent with spectrum.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=581.

Anal. Calc'd for C₃₅ H₄₀ N₄ O₄ : C, 72.39; H, 6.94; N, 9.65. Found: C,72.49; H, 6.68; N, 9.58.

EXAMPLE 2264-(1,1-Dimethylethyl)-N-(5-(2-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-benzamide

The procedure of Example 134 was carried out using equivalent amounts of1,3-dihydro-3(R,S)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-t-butylbenzoylchloride. The product was purified by chromatographyon silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo and crystallized to givethe title compound which was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 96% pure.

MS: Molecular ion at m/e=444.

Anal. Calc'd for C₂₇ H₂₆ FN₃ O₂ : C, 73.12; H, 5.91; N, 9.47. Found: C,73.17; H, 6.28; N, 9.27.

EXAMPLE 2271-(2-Amino-4-methyl-1-oxopentyl)-3-((2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)methyl)-2,3-dihydro-1H-indolehydrochloride

The procedure of Example 2 was carried out in which(1-[(3-[(2,3-dihydro-2-oxo-5-phenyl-1,4-benzodiazepin-3-yl)methyl]-2,3-dihydro-1H-indol-1-yl)carbonyl]-3-methylbutyl]-carbamic acid-1,1-dimethylethyl ester wasreacted with excess HCl gas in ethyl acetate at 0° C. to give the titlecompound as a foam.

NMR: Consistent with structure assignment.

HPLC: Greater than 96% pure.

Anal. Calc.d for C₃₀ H₃₂ N₄ O₂.1.5HCl: C, 67.31; H, 6.31; N, 10.47; Cl,9.94. Found: C, 66.95; H, 6.63; N, 9.97; Cl, 9.73.

EXAMPLE 228(S)-N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-pentylbenzamide

The procedure of Example 134 was carried out using equivalent amounts of3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-n-pentylbenzoylchloride. The product was purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo to givethe title compound which was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=457.

Anal. Calc'd for C₂₈ H₂₈ FN₃ O₂ : C, 73.66; H, 5.98; N, 9.20. Found: C,73.29; H, 6.09; N, 9.25.

EXAMPLE 2292,3-Dihydro-2-oxo-5-phenyl-3-(((phenylmethoxy)carbonyl)amino)-1H-1,4-benzodiazepine-1-propanoicacid ethyl ester

The procedure of Example 134 was carried out using equivalent amounts of1,3-dihydro-3-phenylmethyloxycarbonylamino-5-phenyl-2H-1,4-benzodiazepin-2-oneand ethyl bromopropionate. The product was purified by chromatography onsilica gel (hexane-ethyl acetate elution). The combined productfractions were evaporated to dryness in vacuo and crystallized to givethe title compound which was dried at 65° C.: m.p. 57°-59° C.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=486.

Anal. Calc'd for C₂₈ H₂₇ N₃ O₅ : C, 69.26; H, 5.60; N, 8.65. Found: C,69.11; H, 5.60; N, 8.54.

EXAMPLE 2303-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-propanoicacid ethyl ester

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 251°-253° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=505.

Anal. Calc'd for C₂₀ H₂₅ ClN₄ O₄ : C, 64.22; H, 4.99; N, 11.10. Found:C, 64.02; H, 5.11; N, 10.91.

EXAMPLE 231(2-((5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)amino)-2-oxo-1-(phenylmethyl)ethyl)-carbamic acid 1,1-dimethylethyl ester

The procedure of Example 77 was carried out in which Boc-D-phenylalaninewas coupled to 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one usingdicyclohexylcarbodiimide. Following the identical work-up andpurification procedure of Example 77 gave the analytical product.

NMR: Confirms structure assignment.

HPLC: Greater than 98% pure.

Anal. Calc'd for C₃₀ H₃₁ FN₄ O₄ : C, 67.91; H, 5.89; N, 10.56. Found: C,67.69; H, 6.21; N, 10.85.

EXAMPLE 232(S-(R*,S*))-(2-((5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)amino)-2-oxo-1-(phenylmethyl)ethyl)-carbamicacid 1,1-dimethylethyl ester

The procedure of Example 77 was carried out in which Boc-D-phenylalaninewas coupled to3(S)-(-)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-onewith dicyclohexylcarbodiimide. Following the identical work-up andpurification procedure of Example 77 gave the analytical product.

NMR: Spectrum confirms structure assignment.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=505.

Anal. Calc'd for C₃₀ H₃₁ FN₄ O₄ : C, 67.91; H, 5.89; N, 10.56. Found: C,67.83; H, 6.08; N, 10.25.

EXAMPLE 233(S)-N-(4-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl-Urea

Equimolar amounts of1,3-dihydro-1-methyl-3(S)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct.

NMR: Confirms structure assignment of product.

HPLC: Greater than 95% pure.

MS: Molecular ion at m/e=419.

Anal. Calc'd for C₂₃ H₁₉ ClN₄ O₂ : C, 65.94; H, 4.57; N, 13.38. Found:C, 65.78; H, 4.82; N, 13.34.

EXAMPLE 234(R)-N-(4-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-Urea

Equimolar amounts of1,3-dihydro-1-methyl-3(R)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=419.

Anal. Calc'd for C₂₃ H₁₉ ClN₄ O₂ : C, 65.94; H, 4.57; N, 13.38. Found:C, 66.24; H, 4.57; N, 13.74.

EXAMPLE 235(2,3-Dihydro-1-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-carbamicacid phenylmethyl ester

The procedure of Example 134 was carried out using equivalent amounts of1,3-dihydro-1-chlorocarbonylmethyl-3-(phenylmethyloxycarbonyl)-5-phenyl-2H-1,4-benzodiazepin-2-oneand 1-methylpiperazine. The product was purified by chromatography onsilica gel (hexane-ethyl acetate elution). The combined productfractions were evaporated to dryness in vacuo and crystallized to givethe title compound which was dried at 65° C: m.p. 200°-202° C.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=526.

Anal. Calc'd for C₃₀ H₃₁ N₅ O₄ : C, 68.55; H, 5.94; N, 13.32. Found: C,68.29; H, 5.72; N, 13.21.

EXAMPLE 2361-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)pyrrolidine

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-pyrroidinecarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperatufe. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 264°-266° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=516.

Anal. Calc'd for C₂₈ H₂₆ ClN₅ O₃ : C, 65.18; H, 5.08; N, 13.57. Found:C, 64.94; H, 5.01; N, 13.50.

EXAMPLE 2371-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)-4-methylpiperazine

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-(4-methylpiperazinecarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 278°-280° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=545.

Anal. Calc'd for C₂₉ H₂₉ ClN₆ O₃ : C, 63.91; H, 5.36; N, 15.42. Found:C, 63.72; H, 5.66; N, 15.32.

EXAMPLE 238N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-3-thiophenecarboxamide

The procedure of Example 134 was carried out using equivalent amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and3-thiophenecarbonyl chloride. The product was purified by chromatographyon silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). The combined productfractions were evaporated to dryness in vacuo to give the title compoundwhich was dried at 65° C.

NMR: Consistent with structure.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=393.

Anal. Calc'd for C₂₁ H₁₆ FN₃ O₂ S: C, 64.11; H, 4.10; N, 10.68. Found:C, 63.87; H, 4.44; N, 10.96.

EXAMPLE 2393-(((4-Chlorophenyl)acetyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetic acid ethyl ester

The procedure of Example 134 was carried out using equivalent amounts of3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-chlorophenylacetyl chloride. The product was purified bychromatography on silica gel (hexane-ethyl acetate elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C: m.p.205°-207° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=490.

Anal. Calc'd for C₂₇ H₂₄ ClN₃ O₄ : C, 66.19; H, 4.94; N, 8.58. Found: C,66.18; H, 4.96; N, 8.55.

EXAMPLE 2404-Chloro-N-(2,3-dihydro-2-oxo-5-phenyl-1,4-benzodiazepin-3-yl)-benzeneacetamide

The procedure of Example 134 was carried out using equivalent amounts of3(R,S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and4-chlorophenylacetyl chloride. The product was purified bychromatography on silica gel (hexane-ethyl acetate elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C: m.p.238°-240° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=404.

Anal. Calc'd for C₂₃ H₁₈ ClN₃ O₂ 0.4H₂ O: C, 67.20; H, 4.61; N, 10.22.Found: C, 67.33; H, 4.63; N, 9.95.

EXAMPLE 2412,3-Dihydro-alpha-methyl-2-oxo-5-phenyl-3-((phenylmethoxy)carbonyl)amino-1H-1,4-benzodiazepine-1-aceticacid ethyl ester

A mixture of 72.9 mg (1.51 mmol) NaH (50% oil dispersion) in 30 ml DMFwas stirred at 0° C. for 10 minutes and then treated with a 10 ml DMFsolution containing 530 mg (1.38 mmol)3-benzyloxycarbonylamino-1,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepin-2-one.After stirring 2 hours at 0° C., 0.194 ml (1.49 mmol) ofethyl-2-bromopropionate was added and the reaction allowed to warm toroom temperature while stirring overnight. DMF was removed in vacuo andthe residue treated with H₂ O and extracted 3xCH₂ Cl₂. The organics werecombined, washed 1x H₂ O, 1x brine, dried over Na₂ SO₄, filtered andstripped to dryness. The crude, oily residue was flash chromatographedon silica gel (4% Et₂ O in CH₂ Cl) to give the individual diastereomers.

α-Diastereomer: The title compound was crystallized from ether m.p.147°-148° C. TLC: Rf=0.39 Silica gel (5% Et₂ O in CH₂ Cl₂ ;

NMR: Confirms structure assignment of product.

HPLC: 99.4% single diastereomer (contains 0.6% of oppositediastereomer).

MS: Molecular ion at M+H=486 (FAB).

Anal. Calc'd for C₂₀ H₂₇ N₃ O₅ : C, 69.26; H, 5.61; N, 8.66. Found: C,69.35; H, 5.65; N, 8.45.

EXAMPLE 2422,3-Dihydro-beta-methyl-2-oxo-5-phenyl-3-((phenylmethoxy)carbonyl)amino-1H-1,4-benzodiazepine-1-aceticacid ethyl ester

For the synthesis and isolation of the title compound refer to theprocedure of Example 241.

β-diastereomer: The title compound was provided by flash chromatographyand obtained as a white foam after removal of the solvent: m.p. 65°-75°C.

TLC: Rf=0.33 Silica gel (5% Et₂ O in CH₂ Cl₂);

NMR: Confirms structure assignment of product plus 5% of α-diastereomer.

HPLC: 100% chemically pure; 5.2%/94.8% =α/β Diastereomeric purity.

MS: Molecular ion at M+H=486 (FAB).

Anal. Calc'd for C₂₈ H₂₇ N₃ O₅ : C, 69.26; H, 5.61; N, 8.66. Found: C,69.14; H, 5.81; N, 8.42.

EXAMPLE 2432,3-Dihydro-alpha-methyl-2-oxo-5-phenyl-3-((phenylmethoxy)carbonyl)amino-1H-1,4-benzodiazepine-1-aceticacid

470 mg (0.968 mmol) of2,3-dihydro-alpha-methyl-2-oxo-5-phenyl-3((phenylmethoxy)carbonyl)amino-1H-1,4-benzodiazepine-1-aceticacid ethyl ester was dissolved in 10 ml THF and 1.94 ml (1.94 mmol) of1M NaOH was added. The turbid mixture was stirred overnight at roomtemperature. The PH was adjusted to 3.0 with 6N HCl. THF was removed invacuo and the residue was dissolved in H₂ O and extracted (3x EtOAc).The combined organics were washed (1x H₂ O, 1x brine), dried over Na₂SO₄, filtered and then stripped to dryness in vacuo. The title compoundwas crystallized from Et₂ O: m.p. 223°-225° C.

NMR: Confirms structure assignment of product and verifies presence ofether solvate.

HPLC: 100% pure.

MS: Molecular ion at M+H=458 (FAB).

Anal. Calc'd for C₂₆ H₂₃ N₃ O₅.1/3C₄ H₁₀ O: C, 68.08; H, 5.50; N, 8.72.Found: C, 68.00; H, 5.40; N, 8.98.

Note: The title compound is a mixture of diastereomers.

EXAMPLE 244(1-(2-(Diethylamino)-1-methyl-2-oxoethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-carbamicacid phenylmethyl ester

390 mg (0.853 mmol) of2,3-dihydro-alpha-methyl-2-oxo-5-phenyl-3-((phenylmethoxy)carbonyl)amino-1H-1,4-benzodiazepine-1-aceticacid was suspended in 28 ml toluene, treated with 1.07 ml (14.6 mmol)thionyl chloride, and stirred at 90° C. for 2 hours. The solvent wasremoved in vacuo and the residue treated with fresh toluene. The cyclewas repeated 4 times. The resulting brown oil was dissolved in 5 ml THF,treated with 185 μl (1.79 mmol) of diethylamine and stirred at roomtemperature for 1 hour. The solvent was removed in vacuo, treated with10% Na₂ CO₃ solution and extracted (3x EtOAc). The extracts werecombined, washed (1x H₂ O, 1x brine), dried over Na₂ SO₄, filtered andstripped to dryness in vacuo. Flash chromatography of the crude producton silica gel (10% Et₂ O in CH₂ Cl₂) gave the title compound which wascrystallized from Et₂ O: m.p. 170°-171° C.

NMR: Confirms structure assignment of product.

HPLC: 98.5% pure.

MS: Molecular ion at M+H=513 (FAB).

Anal. Calc'd for C₃₀ H₃₂ N₄ O₄ : C, 70.29; H, 6.29; N, 10.93. Found: C,70.17; H, 6.24; N, 10.94.

Note: The only evidence of diastereomers is observed in the NMR, whichindicates a 1:1 mixture.

EXAMPLE 245(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-carbamicacid-4-nitrophenyl ester

The procedure of Example 134 was carried out using equivalent amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 4-nitrophenylchloroformate. The product was Purified bychromatography on silica gel (5% (v/v) Et₂ O in CH₂ Cl₂ elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C.: m.p.202°-204° C.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=448.

Anal. Calc'd for C₂₃ H₁₇ FN₄ O₅ : C, 61.61; H, 3.82; N, 12.50. Found: C,61.80; H, 4.07; N, 12.26.

EXAMPLE 246N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-oneand 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 271°-273° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=432.

Anal. Calc'd for C₂₄ H₂₁ FN₄ O₃ : C, 66.66; H, 4.89; N, 12.96. Found: C,66.54; H, 5.00; N, 12.79.

EXAMPLE 247N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 245°-246° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=414.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₃ : C, 69.55; H, 5.35; N, 13.52. Found: C,69.23; H, 5.23; N, 13.66.

EXAMPLE 248N-(((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)-4-methylbenzenesulfonamide

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand p-toluenesulfonylchloride were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 244°-246° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 97% pure.

MS: Molecular ion at m/e=463.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₄ S: C, 62.32; H, 4.79; N, 12.11. Found: C,62.44; H, 5.11; N, 12.11.

EXAMPLE 2493-((((4-Chlorophenyl)amino)carbonyl)amino)-N,N,-diethyl-2,3-dihydro-alpha-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide

Under a nitrogen atmosphere, 93.1 mg of 10% Pd on activated carbon wasadded to a 3 ml solution of 4.5% HCO₂ H in MeOH followed by 200 mg(0.390 mmol) of(1-(2-(diethylamino)-1-methyl-2-oxoethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)carbamicacid phenyl methyl ester dissolved in 4 ml of 4.5% HCO₂ H in MeOH. Themixture was stirred 1 hour at room temperature. The solvent was removedin vacuo and the residue was treated with toluene. The solvent was againremoved in vacuo and this cycle was repeated with toluene, 1:1toluene-tetrahydrofuran and finally, with tetrahydrofuran. The crudeamine-formate salt was suspended in 5 ml THF, cooled to 0° C., treatedwith 104 μl (0.746 mmol) of triethylamine followed by 58.4 mg (0.380mmol) of p-chlorophenylisocyanate and allowed to warm to roomtemperature with stirring overnight. The solvent was removed in vacuoand the residue was dissolved in CH₂ Cl₂ and flash chromatographed onsilica gel (20% EtoAc in CH₂ Cl₂) to give the title compound as a whitesolid after trituration with Et₂ O: m.p. 80°-282° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98.4% pure.

MS: Molecular ion at M+H=532 (FAB).

Anal. Calc'd for C₂₉ H₃₀ ClN₅ O₃ : C, 65.46; H, 5.68; N, 13.17. Found:C, 65.21; H, 5.28; N, 12.89.

Note: NMR appears to show a single diastereomer. HPLC shows a singlepeak.

EXAMPLE 250N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-phenylurea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand phenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at roomtemperature. The reaction mixture was allowed to stand for 8 hours andwas then filtered. The collected solids were washed with tetrahydrofuranand dried in vacuo over P₂ O₅ to give the analytical product: m.p.260°-261° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=384.

Anal. Calc'd for C₂₃ H₂₀ N₄ O₂ : C, 71.86; H, 5.24; N, 14.57. Found: C,71.65; H, 5.54; N, 14.76.

EXAMPLE 251N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-phenylmethylurea.

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand phenylmethylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 240°-242° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=398.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₂ : C, 72.34; H, 5.56; N, 14.06. Found: C,71.94; H, 5.88; N, 14.12.

EXAMPLE 252N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-methyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 274°-277° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=398.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₂ : C, 72.34; H, 5.57; N, 14.06. Found: C,72.17; H, 5.28; N, 14.26.

EXAMPLE 253N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methoxvphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalProduct: m.p. 261°-263° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=414.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₃ : C, 69.55; H, 5.35; N, 13.52. Found: C,69.31; H, 4.98; N, 13.56.

EXAMPLE 254N-(2-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 263°-265° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=419.

Anal. Calc'd for C₂₃ H₁₉ ClN₄ O₂ : C, 65.95; H, 4.57; N, 13.38. Found:C, 65.65; H, 4.74; N, 13.46.

EXAMPLE 255N-(4-Bromophenyl-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2-chlorophenylisacyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 286°-287° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=463.

Anal. Calc'd for C₂₃ H₁₉ BrN₄ O₂ : C, 59.62; H, 4.13; N, 12.09. Found:C, 59.74; H, 4.32; N, 12.14.

EXAMPLE 256N-(4-Nitrophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 292°-293° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=429.

Anal. Calc'd for C₂₃ H₁₉ N₅ O₄ : C, 64.33; H, 4.46; N, 16.31. Found: C,64.05; H, 4.39; N, 16.38.

EXAMPLE 257N-(3,4-Dichlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 3,4-dichlorophenylisocyanate were mixed in 8 ml of drytetrahydrofuran at room temperature. The reaction mixture was allowed tostand for 8 hours and was then filtered. The collected solids werewashed with tetrahydrofuran and dried in vacuo over P₂ O₅ to give theanalytical product: m.p. 274°-276° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=453.

Anal. Calc'd for C₂₃ H₁₈ Cl₂ N₄ O₂ : C, 60.94; H, 4.00; N, 12.36 Found:C, 61.01; H, 4.22; N, 12.48.

EXAMPLE 258N-(2,4-Dichlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2,4-dichlorophenylisocyanate were mixed in 8 ml of drytetrahydrofuran at room temperature. The reaction mixture was allowed tostand for 8 hours and was then filtered. The collected solids werewashed with tetrahydrofuran and dried in vacuo over P₂ O₅ to give theanalytical product: m.p. 285°-287° C. (d).

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=453.

Anal. Calc'd for C₂₃ H₁₈ Cl₂ N₄ O₂ : C, 60.94; H, 4.00; N, 12.36. Found:C, 61.30; H, 4.29; N, 12.35.

EXAMPLE 259N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-fluorophenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 4-fluorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 269°-270° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=402.

Anal. Calc'd for C₂₃ H₁₉ FN₄ O₂ : C, 68.65; H, 4.76; N, 13.92. Found: C,68.48; H, 4.71; N, 13.98.

EXAMPLE 260N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(1,1-dimethylethyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand t-butylisocyanate were mixed in 8 ml of dry tetrahydrofuran at roomtemperature. The reaction mixture was allowed to stand for 8 hours andwas then filtered. The collected solids were washed with tetrahydrofuranand dried in vacuo over P₂ O₅ to give the analytical product: m.p.281°-282° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=364.

Anal. Calc'd for C₂₁ H₂₄ N₄ O₂ : C, 69.21; H, 6.64; N, 15.37. Found: C,69.11; H, 6.40; N, 15.44.

EXAMPLE 261N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-((R)1-phenylethyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand (R)-(+)-α-methylbenzylisocyanate were mixed in 8 ml of drytetrahydrofuran at room temperature. The reaction mixture was allowed tostand for 8 hours and was then filtered. The collected solids werewashed with tetrahydrofuran and dried in vacuo over P₂ O₅ to give theanalytical product as a mixture of diastereomers: m.p. 146°-150° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=412.

Anal. Calc'd for C₂₅ H₂₄ N₄ O₂.0.2C₄ H₈ O: C, 72.58; H, 6.04; N, 13.12.Found: C, 72.20; H, 5.75; N, 13.36.

EXAMPLE 262N-Cyclohexyl-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand cyclohexylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 287°-288° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=390.

Anal. Calc'd for C₂₃ H₂₆ N₄ O₂ : C, 70.75; H, 6.71; N, 14.35. Found: C,70.39; H, 6.43; N, 14.44.

EXAMPLE 263N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 3-methylphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 207°-209° C.

NMR: Confirms structure assignment of product

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=398.

Anal. Calc'd for C₂₃ H₂₂ N₄ O₂ : C, 72.34; H, 5.56; N, 14.06. Found: C,72.26; H, 5.22; N, 14.23.

EXAMPLE 264N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-nitrophenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 3-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 288°-289° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=429.

Anal. Calc'd for C₂₃ H₁₉ N₅ O₄ : C, 64.33; H, 4.46; N, 16.31. Found: C,64.49; H, 4.22; N, 15.94.

EXAMPLE 265N-(3-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 3-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 233°-234° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=419.

Anal. Calc'd for C₂₃ H₁₉ ClN₄ O₂ : C, 65.95; H, 4.57; N, 13.38. Found:C, 65.93; H, 4.65; N, 13.14.

EXAMPLE 266(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea

Equimolar amounts of3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 216°-219° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=414.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₃ : C, 69.55; H, 5.35; N, 13.52. Found: C,69.61; H, 5.62; N, 13.57.

EXAMPLE 267(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea

Equimolar amounts of3-(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 216°-219° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=414.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₃ : C, 69.55; H, 5.35; N, 13.52. Found: C,69.90; H, 5.79; N, 13.53.

EXAMPLE 268(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-methoxybenzeneacetamide

The procedure of Example 134 was carried out using equivalent amounts of3-(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and3-methoxyphenylacetylchloride. The product was purified bychromatography on silica gel (hexane-ethyl acetate elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C.: m.p.198°-199° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=413.

Anal. Calc'd for C₂₅ H₂₃ N₃ O₃ : C, 72.62; H, 5.61; N, 10.16. Found: C,73.00; H, 5.70; N, 10.25.

EXAMPLE 269(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-methoxybenzenacetamide

The procedure of Example 134 was carried out using equivalent amounts of3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and3-methoxyphenylacetyl chloride. The product was purified bychromatography on silica gel (hexane-ethyl acetate elution). Thecombined product fractions were evaporated to dryness in vacuo andcrystallized to give the title compound which was dried at 65° C.: m.p.198°-199° C.

NMR: Consistent with structure.

HPLC: Greater than 98% pure.

MS: molecular ion at m/e=413.

Anal. Calc'd for C₂₅ H₂₃ N₃ O₃ : C, 72.62: H, 5.61; N, 10.16. Found: C,72.29: H, 5.60; N, 10.15.

EXAMPLE 270N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-nitrophenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 260°-261° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=429.

Anal. Calc'd for C₂₃ H₁₉ N₅ O₄ : C, 64.33; H, 4.46; N, 16.31. Found: C,64.16; H, 4.37; N, 16.40.

EXAMPLE 271N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-fluorophenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2-fluorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 252°-254° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=402.

Anal. Calc'd for C₂₃ H₁₉ FN₄ O₂ : C, 68.65; H, 4.76; N, 13.92. Found: C,69.00; H, 5.00; N, 13.78.

EXAMPLE 272N-(3-Bromophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2-bromophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 219°-221° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=463.

Anal. Calc'd for C₂₃ H₁₉ BrN₄ O₂ : C, 59.62; H, 4.13; N, 12.09. Found:C, 59.78; H, 4.26; N, 12.01.

EXAMPLE 273N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-1-naphthalenyl-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 1-naphthylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 234°-235° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=434.

Anal. Calc'd for C₂₇ H₂₂ N₄ O₂ : C, 74.64; H, 5.10; N, 12.89. Found: C,74.64; H, 5.03; N, 12.69.

EXAMPLE 274N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-vl)-N'-(3,5-dimethylphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 3,5-dimethoxyphenylisocyanate were mixed in 8 ml of drytetrahydrofuran at room temperature. The reaction mixture was allowed tostand for 8 hours and was then filtered. The collected solids werewashed with tetrahydrofuran and dried in vacuo over P₂ O₅ to give theanalytical product: m.p. 267°-269° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=444.

Anal. Calc'd for C₂₅ H₂₄ N₄ O₄.1/4H₂ O: C, 66.88; H, 5.50; N, 12.48.Found: C, 66.77; H, 5.43; N, 12.12.

EXAMPLE 275N-(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 254°-255° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure; R_(f) =0.42 (5% CH₃ OH in CH₂ C₁₂).

MS: Molecular ion at m/e=400.

Anal. Calc'd for C₂₂ H₂₆ N₄ O₃.0.15(C₂ H₅)₂ O: C, 68.87; H, 5.27; N,13.62. Found: C, 68.50; H, 5.09; N, 13.63.

EXAMPLE 276(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-chlorophenyl)-urea

Equimolar amounts of3(S)-(-)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 212°-214° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=419.

Anal. Calc'd for C₂₃ H₁₉ ClN₄ O₂ : C, 65.95; H, 4.57; N, 13.38. Found:C, 66.17; H, 4.86; N, 13.23.

EXAMPLE 277N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-phenylthiourea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand Phenylisothiocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 209°-211° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=401.

Anal. Calc'd for C₂₃ H₂₀ N₄ OS: C, 68.98; H, 5.03; N, 13.99. Found: C,68.97; H, 5.25; N, 14.07.

EXAMPLE 278N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-methoxyphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneand 2-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 258°-260° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=414.

Anal. Calc'd for C₂₄ H₂₂ N₄ O₃.1/2H₂ O: C, 68.08; H, 5.47; N, 13.23.Found: C, 68.18; H, 5.33; N, 13.05.

EXAMPLE 2791-Pivaloyloxymethyloxycarbonylmethyl-1,3-dihydro-3-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one

A mixture of1-carboxymethyl-1,3-dihydro-3-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one(85 mg, 0.20 mmol), pivaloyloxymethylchloride (32 μl, 0.22 mmol) andtriethylamine (28 μl, 0.20 mmol) was combined in 2 ml of drydimethylformamide and allowed to stand at room temperature for 48 hours.Solvent was removed under reduced pressure and the residue partitionedbetween ethyl acetate and water. Extractive work-up gave 100 mg of crudeProduct which was chromatographed on silica gel (CH₃ OH-CHCl₃, 3:97 v/velution) to give a white solid after trituration with ether: m.p.225°-226° C.

NMR: Spectrum confirs structure assignment.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=567.

Anal. Calc'd for C₃₂ H₃₀ N₄ O₆ :

C, 67.83; H, 5.34; N, 9.89. Found: C, 67.61; H, 5.42; N, 9.63.

EXAMPLE 280N-(2,3-Dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea

Equimolar amounts of3(R,S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-thione and3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 229°-231° C. (d).

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=417 (FAB).

Anal. Calc'd for C₂₃ H₂₀ N₄ O₂ S: C, 66.33; H, 4.84; N, 13.45. Found: C,65.99; H, 4.90; N, 13.34.

EXAMPLE 281(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea

Equimolar amounts of3(R)-amino-1,3-dihydro-1-5-pheny,l:-2H-1,4-benzodiazepin-2-one and3-methylphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 208°-210° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=399 (FAB).

Anal. Calc'd for C₂₃ H₂₂ N₄ O₂ : C, 72.34; H, 5.56; N, 14.06. Found: C,72.12; H, 5.84; N, 14.04.

EXAMPLE 282(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-bromophenyl)-urea

Equimolar amounts of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and3-bromophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 194°-196° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=463.

Anal. Calc'd for C₂₃ H₁₉ BrN₄ O₂ : C, 59.62; H, 4.13; N, 12.09. Found:C, 59.67; H, 4.17; N, 11.72.

EXAMPLE 283(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-iodobenzamide

Equimolar amounts of3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,o-iodo-benzoylchloride and triethylamine were mixed at room temperatureand stirred 1 hour. Flash chromatography of the reaction solution onsilica gel (5% Et₂ O in (CH₂ Cl₂) provided the title compound as acrystalline solid from EtOAc: m.p. 115°-120° C. (physical change),173°-175° C. (melt).

NMR: Confirms structure assignment of product and verifies presence ofEtOAc solvate.

HPLC: Greater than 99.6% pure.

MS: Molecular ion at m/e=496 (FAB).

Anal. Calc'd for C₂₃ H₁₈ IN₃ O₂.0.3C₄ H₈ O₂ : C, 55.71; H, 3.94; N,8.05. Found: C, 55.56; H, 3.81; N, 8.37.

[α]_(D) ²⁵ =-85.5° (conc. =2.9 mg/ml CH₂ Cl₂).

EXAMPLE 2841-{[3-[(((3-Methoxyphenyl)amino)carbonyl)amino]-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pyrrolidine

Equimolar amounts of1-{[(3-amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pryrrolidineand 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 193°-194° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=512.

Anal. Calc'd for C₂₉ H₂₉ N₅ O₄ : C, 68.09; H, 5.71; N, 13.69. Found: C,68.14; H, 5.65; N, 13.24.

EXAMPLE 2853-{[((3-Methoxyphenyl)amino)carbonyl)amino]-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide

Equimolar amounts of3-amino-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamideand 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 222°-224° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=514.

Anal. Calc'd for C₂₉ H₃₁ N₅ O₄.1/4H₂ O: C, 67.26; H, 6.13; N, 13.52.Found: C, 67.22; H, 6.04; N, 13.30.

EXAMPLE 2863-{[((2-Chlorophenyl)amino)carbonyl]amino}-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide

Equimolar amounts of3-amino-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamideand 2-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuranat room temperature. The reaction mixture was allowed to stand for 8hours and was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 173°-175° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=518.

Anal. Calc'd for C₂₈ H₂₈ ClN₅ O₃.1/4H₂ O: C, 64.35; H, 5.49; N, 13.40.Found: C, 64.31; H, 5.41; N, 13.22.

EXAMPLE 2873-N-(2,3-Dihydro-9-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazeoin-3-yl)-1H-indole-2-carboxamide

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-9-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,indole-2-carbonyl chloride, and triethylamine were mixed at roomtemperature and stirred for 30 minutes. Flash chromatography of thereaction solution on silica gel (20% Et₂ O in CH₂ Cl₂) provided thetitle compound as a crystalline solid from Et₂ O: m.p. 229°-232° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99.7% pure.

MS: Molecular ion at m/e=408.

Anal. Calc'd for C₂₅ H₂₀ N₄ O₂ : C, 73.51; H, 4.94; N, 13.72. Found: C,73.44; H, 5.18; N, 13.35.

EXAMPLE 288N-(3-Methoxyphenyl)-N'-(2,3-dihydro-9-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-9-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,3-methoxy-phenylisocyanate and triethylamine were mixed in THF at 0° C.and stirred 40 minutes. Removal of THF in vacuo gave a residue which wascrystallized from MeOH: m.p. 250°-252° C.

NMR: Confirms structure assignment of product and verifies presence ofCH₃ OH solvate.

HPLC: Greater than 96.9% pure.

MS: Molecular ion at m/e=415 (FAB).

Anal. Calc'd for C₂₄ H₂₂ N₄ O₃.0.1CH₄ O: C, 69.30; H, 5.41; N, 13.42.Found: C, 69.00; H, 5.57; N, 13.31.

EXAMPLE 2893-N-(2,3-Dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-1,9-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one,indole-2-carbonyl chloride and triethylamine were mixed at roomtemperature and stirred 30 minutes. Flash chromatography of the reactionsolution on silica gel (7% Et₂ O in CH₂ Cl₂) provided the title compoundas a crystalline solid from Et₂ O: m.p. 286°-289° C.

NMR: Confirms structure assignment of product and verifies presence ofEt₂ O solvate.

HPLC: Greater than 96.2% pure.

MS: Molecular ion at m/e =422.

Anal. Calc'd for C₂₆ H₂₂ N₄ O₂.1/3C₄ H₁₀ O: C, 73.42; H, 5.71; N, 12.54.Found: C, 73.08; H, 5.68; N, 12.87.

EXAMPLE 290N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-1,9-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one,3-methoxyphenylisocyanate and triethylamine were mixed in THF at 0° C.and stirred 20 minutes. Removal of THF in vacuo, dissolution of theresidue in CH₂ Cl₂ and flash chromatography on silica gel (12% Et₂ O inCH₂ Cl₂) gave the title compound which was crystallized as a whitefluffy solid from Et₂ O: m.p. 215°-217° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98.8% pure.

MS: Molecular ion at m/e=429.

Anal. Calc'd for C₂₅ H₂₅ N₄ O₃ : C, 70.07; H, 5.65; N, 13.08. Found: C,70.08; H, 5.88; N, 13.07.

EXAMPLE 2913-N-(2,3-Dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-1-methyl-5-(p-tolyl)-2H-1,4-benzodiazepin-2-one,indole-2-carbonyl chloride, and triethylamine were mixed at roomtemperature and stired 30 minutes. Flash chromatography of the reactionsolution on silica gel (5% Et₂ O in CH₂ Cl₂) provided the title compoundas a crystalline solid from Et₂ O: m.p. 280°-282° C.

NMR: Confirms structure assignment of product and verifies presence ofEt₂ O solvate.

HPLC: Greater than 99.2% pure.

MS: Molecular ion at m/e=422.

Anal. Calc'd for C₂₆ H₂₂ N₄ O₂.0.15C₄ H₁₀ O: C, 73.68; H, 5.46; N,12.92. Found: C, 73.97; H, 5.44; N, 13.09.

EXAMPLE 292N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-1-methyl-5-(p-tolyl)-2H-1,4-benzodiazepin-2-one,3-methoxyphenylisocyanate, and triethylamine were mixed in THF at 0° C.and stirred 20 minutes. Removal of THF in vacuo and crystallization fromMeOH gave the title compound: m.p. 240°-242° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99.9% pure.

MS: Molecular ion at m/e=428.

Anal. Calc'd for C₂₅ H₂₄ N₄ O₃ : C, 70.07; H, 5.65; N, 13.08. Found: C,69.86; H, 5.62; N, 12.83.

EXAMPLE 293(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea

Equimolar amounts of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and4-methylPhenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 233°-235° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=399 (FAB).

Anal. Calc'd for C₂₄ H₂₂ N₄ O₂ : C, 72.34; H, 5.57; N, 14.06. Found: C,72.62; H, 5.76; N, 14.24.

EXAMPLE 2943-N-(2,3-Dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-1,8-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one,indole-2-carbonyl chloride, and triethylamine were mixed at roomtemperature and stirred 30 minutes. Flash chromatography of the reactionsolution on silica gel (7% Et₂ O in CH₂ Cl₂) provided the title compoundas a crystalline solid from Et₂ O: m.p. 291°-294° C.

NMR: Confirms structure assignment of product and verifies presence ofEt₂ O solvate.

HPLC: Greater than 99.5% pure.

MS: Molecular ion at m/e=422.

Anal. Calc'd for C₂₆ H₂₂ N₄ O₂.0.25C₄ H₁₀ O: C, 73.53; H, 5.60; N,12.71. Found: C, 73.56; H, 5.71; N, 12.87.

EXAMPLE 295N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea

Equimolar amounts of3-(R,S)-amino-1,3-dihydro-1,8-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one,3-methoxyphenylisocyanate, and triethylamine were mixed in THF at 0° C.and stirred 20 minutes. Removal of THF in vacuo and crystallization fromMeOH gave the title compound: m.p. 184°-188° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 99.9% pure.

MS: Molecular ion at m/e=428.

Anal. Calc'd for C₂₅ H₂₄ N₄ O₃ : C, 70.07; H, 5.65; N, 13.08. Found: C,70.36; H, 6.01; N, 13.08.

EXAMPLE 296(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-chloroohenyl)-urea

Equimolar amounts of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and3-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran atroom temperature. The reaction mixture was allowed to stand for 8 hoursand was then filtered. The collected solids were washed withtetrahydrofuran and dried in vacuo over P₂ O₅ to give the analyticalproduct: m.p. 178°-180° C.

NMR: Confirms structure assignment of product.

HPLC: Greater than 98% pure.

MS: Molecular ion at m/e=419 (FAB).

Anal. Calc'd for C₂₃ H₁₉ ClN₄ O₂.0.2H₂ O: C, 65.39; H, 4.63; N, 13.26.Found: C, 65.20; H, 4.67; N, 13.17.

EXAMPLE 297N-(4-Chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-acetamide

The lithium salt of1,3-dihydro-1-methyl-phenyl-2H-1,4-benzodiazepin-2-one (0.5 g, 2 mmole)was made according to the procedure of Example 47. To the anion solutionwas added ethyl bromoacetate (0.33 g, 2 mmole). After stirring at roomtemperature for 1/2 hour, the reaction was worked up as described inExample 47 to give the 3-ethoxycarbonylmethyl benzodiazepine.

This compound (120 mg, 0.36 mmole)was combined with aqueous sodiumhydroxide solution (0.4 ml/lM solution, 0.4 mmole) in 2 ml of methanolplus 1.5 mg of tetrahydrofuran and stirred at room temperature for 18hours. The mixture was adjusted to pH 5 with 1N HCl and filtered toprovide the 3-carboxymethylbenzodiazepine. The entire lot of thismaterial was stirred in DMF (4 ml) in an ice bath. N-Methylmorpholine(55 mg, 0.5 mmole) was added, followed by isobutylchlorocarbonate (70mg, 0.5 mmole). The mixture was stirred 1/2 hour in the cold, thentreated with a solution of 4-chloroaniline (76 mg, 0.6 mmole) in DMF (3ml). The mixture was stirred at room temperature for 3 days, thenevaporated in vacuo. The residue was combined with water and extractedwith CH₂ Cl₂ (3×10 ml). The CH₂ Cl₂ extracts were combined, washed withdilute citric acid, then sodium bicarbonate solution, dried over sodiumsulfate, filtered, and evaporated to dryness in vacuo. The residue waschromatographed on silica gel (eluted with 2% (v/v) methanol in CH₂ Cl₂)to give the title compound which was dried at 90° C.: m.p. 238°-240° C.

NMR: Consistent with structure.

HPLC: Greater than 99% pure.

MS: Molecular ion at m/e=417.

Anal. Calc'd for C₂₄ H₂₀ ClN₃ O₂ : C, 68.98: H, 4.82; N, 10.06. Found:C, 68.82: H, 4.78; N, 9.86.

What is claimed is:
 1. A compound of Formula II: ##STR130## wherein R¹is H, C₁ -C₆ linear or branched alkyl, loweralkenyl, lower alkynyl,--X¹² COOR⁶, --X¹¹ -cycloloweralkyl, --X¹² NR⁴ R⁵, --X¹² CONR⁴ R⁵, --X¹²CN, or --X¹¹ CX₃ ¹⁰ ;R² is H, loweralkyl, substituted or unsubstitutedphenyl (wherein the substitutents may be 1 or 2 of halo, loweralkyl,loweralkoxy, loweralkylthio, carboxyl, carboxyloweralkyl, nitro, --CF³,or hydroxy), 2-, 3-, 4-pyridyl, ##STR131## --X¹² SCH₃, --x¹² SOCH₃,--X¹² SO₂ CH₃, or --X¹² COOR⁶ ; ³ is ##STR132## with the priviso thatR¹⁰ is not H or --CH₃ when R³ is ##STR133## R⁴ and R⁵ are independentlyR⁶ or in combination with the N of the NR⁴ R⁵ group form anunsubstituted or mono or disubstituted, saturated or unsaturated, 4-7membered heterocyclic ring, or benzofused ,4-7 membered heterocyclicring wherein said heterocyclic ring or said benzofused heterocyclic ringmay contain a second heteroatom selected from O and NCH₃ and thesubstituent(s) is/are independently selected from C₁ -C₄ alkyl; R⁶ is H,loweralkyl, cycloloweralkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted phenylloweralkyl wherein the phenyl orphenylloweralkyl substituents may be 1 or 2 of halo, loweralkyl,loweralkoxy, nitro, or CF₃ ; R⁷ is α- or β-naphthyl, substituted orunsubstituted phenyl (wherein the substituents may be independently 1 to2 of halo, --NO₂, --OH,--X¹¹ NR⁴ R⁵, loweralkyl, CF₃, CN, SCF₃,C.tbd.CH, CH₂ SCF₃, ##STR134## OCHF₂, SH, SPh, PO₃ H, loweralkoxy,loweralkylthio or COOH), 2-, 3-, 4- pyridyl, ##STR135## R⁸ is H,loweralkyl, cycloloweralkyl, --X¹² CONH₂, --X¹² COOR⁶, --X¹²-cycloloweralkyl, --X¹² NR⁴ R⁵, ##STR136## R⁹ and R¹⁰ are independentlyH, --OH, or --CH₃ ; R¹¹ and R¹² are independently loweralkyl orcycloloweralkyl; R¹³ is H, loweralkyl, acyl, O, or cycloloweralkyl; R¹⁴is loweralkyl or phenylloweralkyl; R¹⁵ is H, loweralkyl, ##STR137## or--NH₂ ; R¹⁶ alpha or beta naphthyl or 2-indolyl; R¹⁸ is H or loweralkyl;p is 0 when its adjacent --- is unsaturated and 1 when its adjacent ---is saturated except that when R¹³ is O, p=1 and --- is unsaturated; q is0-4; r is 1 or 2; X¹ is H, --NO₂, CF₃ CN, OH, loweralkyl, halo,loweralkylthio, loweralkoxy, --X¹¹ COOR⁶, or --X¹¹ NR⁴ R⁵, X² and X³ areindependently H, --OH,--NO₂, halo, loweralkylthio, loweralkyl, orloweralkoxy; X⁴ is S, O, CH₂, or NR⁸ ; X⁵ is H, CF₃, CN, --COOR⁶, NO₂,or halo; X⁶ is O or HH; X⁷ is O, S, HH, or NR¹⁵ with the proviso that X⁷can be NR¹⁵ only when R¹ is not H; X⁸ is H, loweralkyl; X⁹ and X_(a) ⁹are independently NR¹⁸ or O; X¹⁰ is F, Cl, or Br; X¹¹ is absent or C₁₋₄linear or branched alkylidene; X¹² is C₁₋₄ linear or branchedalkylidene; --- is a saturated or unsaturated bond; with the provisothat when X_(r) ¹ is Cl in the seven position, R¹ is H and R² isunsubstituted phenyl, then R³ is not NHCO(CH₂)₂ C₆ H₅ or NHCOC₆ H₅ orpharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein:R¹ is H, C₁ -C₆ linear or branched alkyl, --X¹² COOR⁶, --X¹¹-cycloloweralkyl, X¹² NR⁴ R⁵ or --X¹² CONR⁴ R⁵ ; R² is substituted orunsubstituted phenyl (wherein the substitutents may be 1 or 2 of halo,loweralkyl, loweralkoxy, loweralkylthio, carboxyl, carboxyloweralkyl,nitro, --CF₃, or hydroxy), 2-, 3-, or 4- pyridyl, ##STR138## R⁴ and R⁵are independently R⁶ or in combination with the N of the NR⁴ R⁵ groupform an unsubstituted or mono or disubstituted, saturated orunsaturated, 4-7 membered heterocyclic ring, or benzofused 4-7 memberedheterocyclic ring wherein said heterocyclic ring or said benzofusedheterocyclic ring may contain a second heteroatom selected from O andNCH₃ and the substituent(s) is/are independently selected from C₁ -C₄alkyl; R⁶ is H, C₁₋₄ straight or branched-chain alkyl or C₃ -C₆-cycloalkyl R⁷ is α- or β-naphthyl, substituted or unsubstituted phenyl(wherein the substituents may be 1 to 2 of halo, --NO₂, --OH, --X¹¹ NR⁴R⁵, loweralkyl, CF₃, CN, SCF₃, ##STR139## SH, SPh, loweralkoxy,loweralkylthio, or carboxy), 2-, 3-, 4-pyridyl, ##STR140## R⁸ is H,loweralkyl or cycloloweralkyl; R⁹ and R¹⁰ are independently H, --OH, or--CH₃ ; R¹³ is H, loweralkyl, acyl, O, or cycloloweralkyl; R¹⁸ is H orloweralkyl; p is 0 when its adjacent --- is unsaturated and 1 when itsadjacent --- is saturated except that when R¹³ is O, p=1 and --- isunsaturated; q is 0-2; r is 1 or 2; X¹ is H, --NO₂, CF₃, CN, loweralkyl,halo, loweralkylthio or --X¹¹ COOR⁶ ; X² and X³ are independently H,--NO₂, halo, loweralkylthio, loweralkyl, or loweralkoxy; X⁴ is S, O, orNR⁸ ; X⁵ is H, CF₃, CN, --COOR⁶, NO₂, or halo; X⁶ is O or HH; X⁷ is O,S; X⁹ and X_(a) ⁹ are independently NR¹⁸, or O; X¹¹ is absent or C₁₋₄linear alkylidene; X¹² is C₁₋₄ linear or branched alkylidene; --- is asaturated or unsaturated bondor pharmaceutically acceptable saltthereof.
 3. A compound of claim 2 wherein:R¹ is H, C₁₋₃ linear orbranched alkyl, --X¹² COOR⁶, --X¹² CONR⁴ R⁵, R² is substituted orunsubstituted phenyl (wherein the substitutents may be 1 or 2 of halo,loweralkyl, carboxyl, nitro or --CF₃); --X¹² COOR⁶ ; 2-, 3-, 4- pyridyl;R³ ##STR141## R⁴ and R⁵ are independently R⁶ or in combination with theN of the NR⁴ R⁵ group form an unsubstituted or mono or disubstituted,saturated or unsaturated, 4-7 membered heterocyclic ring, or benzofused4-7 membered heterocyclic ring wherein said heterocyclic ring or saidbenzofused heterocyclic ring may contain a second heteroatom selectedfrom O and NCH₃ and the substituent(s) is/are independently selectedfrom C₁₋₄ alkyl; R⁶ is H, C₁₋₄ straight or branched-chain alkyl; R⁷ isα- or β-naphthyl, substituted or unsubstituted phenyl (wherein thesubstituents may be 1 to 2 of halo, --NO₂, --OH, --NR⁴ R⁵, loweralkyl,CF₃, CN, or loweralkoxy), 2-, 3-, 4-pyridyl, ##STR142## R⁹ and R¹⁰ areindependently H, or --OH; p is 0 when its adjacent --- is unsaturatedand 1 when its adjacent --- is saturated, the p of (R¹³)_(p) is 0; r is1 or 2; X¹ is H, --NO₂, CF₃, loweralkyl or halo; X² and X³ areindependently H, --NO₂, halo, loweralkyl, or loweralkoxy; X⁴ is O or NR⁸; X⁷ is O or S, X¹² is C₁₋₂ linear or branched chain alkylidene; --- isa saturated or unsaturated bond;or the pharmaceutically acceptable saltthereof.
 4. A compound of claim 3 wherein:R¹ is H, C₁ -C₂ linear alkyl,--X¹² COOR⁶, --X¹² CONR⁴ R⁵ ; R² is substituted or unsubstituted phenyl(wherein the substitutent may be halo, loweralkyl, nitro, --CF₃), 2-,3-, 4-pyridyl, or X¹² COOR⁶ ; R³ is ##STR143## R⁴ and R⁵ areindependently R⁶ or in combination with the N of the NR⁴ R⁵ group forman unsubstituted or mono or disubstituted, saturated or unsaturated, 4-7membered heterocyclic ring, or benzofused 4-7 membered heterocyclic ringwherein said heterocyclic ring or said benzofused heterocyclic ring maycontain a second heteroatom selected from O and NCH₃ and thesubstituent(s) is/are independently selected from C₁₋₄ alkyl; R⁶ is H,C₁ -C₃ straight chain alkyl; R⁷ is α- or β-naphthyl, substituted orunsubstituted phenyl (wherein the substituents may be 1 to 2 of halo,--NO₂, NH₂, methyl, ethyl, CF₃, CN, or loweralkoxy), 2-, 3-, 4-pyridyl,##STR144## R¹⁰ is H, or OH; p is 1 of (R¹⁰)_(p) and 0 of (R⁹)_(p) and(R¹³)_(p), --- at 4,5 is unsaturated and --- at 3,4 is saturated; r is 1or 2; X¹ is H, --NO₂, CF₃, loweralkyl or halo; X² is H, --NO₂, halo orloweralkyl; X⁴ is O, NH, NCH₃ ; X⁷ is O or S; X¹² is C₁₋₂ linearalkylidene;or pharmaceutically acceptable salt thereof.
 5. A compound ofclaim 4 wherein:R¹ is H, CH₃, CH₂ CH₃, CH₂ COOH, CH₂ COOEt, ##STR145##R² is phenyl, 2-F-phenyl, 4-CH₃ -phenyl, 2-, 3-, or 4-pyridyl; R³ is##STR146## R¹⁰ is H or --OH; p is 1 of (R¹⁰)_(p) and 0 of (R⁹)_(p) and(R¹³)_(p) ; r is 1; X¹ is H, 7-Cl, 8-CH₃, 9-CH₃ ; X⁷ is O or S; --- at4, 5 is unsaturated and 3, 4 is saturated;or the pharmaceuticallyacceptable salt thereof;
 6. A compound of claim 1 whichis:3(R)-N-(4-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl)urea,3-Benzoyl-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,5-(2-Fluorophenyl)-1,3-dihydro-3-hydroxy-3-(4-methoxybenzoyl)-1-methyl-2H-1,4-benzodiazepin-2-one,N-(2,3-Dihydro-1-methyl-2-oxo-5(3-methylphenyl)-1H-1,4-benzodiazepin-3-yl)-N'-(phenylmethyl)urea,N-(2,3-Dihydro-1-ethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)urea,3-(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(3-methoxyphenyl)-2-propenamide,3-((((4-Chlorophenyl)amino)carbonyl)amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-propanoicacid ethyl ester,3(RS)-1,3-dihydro-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,1-Carboxymethyl-1,3-dihydro-3(RS)-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-3(RS)-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-dihydro-1-methyl-3(RS)-[2-(1-methylindole)carbonylamino]-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-1-methyl-3(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)3(RS)-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)-1-methyl-3(RS)-[2'-(1'-methylindole)carbonylamino]-2H-1,4-benzodiazepin-2-one,3(S)-(-)-1,3-Dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,(S)-(+)-1,3-Dihydro-3-(4-chlorobenzoylamino)-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,3(S)-(-)-1,3-Dihydro-3-(4-bromobenzoylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,1-Carboxymethyl-1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one, 1.3-Dihydro-3-(RS)-(5-fluoroindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-3-(RS)-(1-methylindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-benzofurancarbonylamino)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-1-methyl-3-(RS)-(4-chlorophenylcarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-3-(3-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-3-(4-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(4-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(3-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indole)carbonylamino-2H-1,4-benzodiazepin-2-thione,3(S)-(2-Indolecarbonyl)amino-1,3-dihydro-5-phenyl-2H-1,4,-benzodiazepin-2-one,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-propenamide,3-((((4-Chlorophenyl)amino)carbonyl)amino)-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,5-(2-Fluorophenyl)-2,3-dihydro-3-((1H-indol-2-ylcarbonyl)amino)-2-oxo-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,4-Bromo-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-bezamide,N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,(S)-N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)benzamide,3-((((4-Chlorophenyl)amino)carbonyl)amino)-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,1-((3-((((4-Chlorophenyl)amino)carbonyl)amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)pyrrolidine,1-((3-((((4-Chlorophenyl)amino)carbonyl)amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)-4-methylpiperazine,3-(((4-Chlorophenyl)acetyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-phenylurea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea,N-(2-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,N-(4-Nitrophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,N-(2,4-Dichlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-nitrophenyl)-urea,N-(3-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-Phenyl-1H-1,4-benzodiazepin-3-yl)urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-(2-nitrophenyl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-fluorophenyl)-urea,N-(3-Bromophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-1-naphthalenyl-urea,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-chlorophenyl)-urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-bromophenyl)-urea,1-{[3-[(((3-Methoxyphenyl)amino)carbonyl)amino]-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pyrrolidine,3-{[((3-Methoxyphenyl)amino)carbonyl)amino]-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,3-{[((2-Chlorophenyl)amino)carbonyl]amino}-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,3-N-(2,3-Dihydro-9-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,3-N-(2,3-Dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,3-N-(2,3-Dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea,3-N-(2,3-Dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-ureaor(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-chlorophenyl)-urea.7. A compound of claim 6 whichis:3(RS)1,3-Dihydro-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,1-Carboxymethyl-1,3-dihydro-3(RS)-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-3(RS)-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-dihydro-1-methyl-3(RS)-[2-(1-methylindole)carbonylamino]-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-1-methyl-3(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2one,1,3-Dihydro-5-(2-fluorophenyl)-1-methyl-3(RS)-[2'-(1'-methylindole)carbonylamino]-2H-1,4-benzodiazepin-2-one,(S)-(-)-1,3-Dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-1,3-Dihydro-3-(4-chlorobenzoylamino)-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,(S)-(-)--1,3-Dihydro-3-(4-bromobenzoylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-3-(RS)-(4-chlorophenylcarbonyl)amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,1-Carboxymethyl-1,3-dihydro-5-(2-fluorophenyl)-3(RS)-(2-indolecarbonylamino)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-3-(RS)-(5-fluoroindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-3-(RS)-(1-methylindole-2-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one, 1.3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-benzofurancarbonylamino)-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-1-methyl-3-(RS)-(4-chlorophenylcarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one,(S)-(+)-3-(3-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,(S)-(+)-3-(4-Bromobenzoylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(4-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(3-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,1,3-Dihydro-5-(2-fluorophenyl)-3-(RS)-(2-indole)carbonylamino-2H-1,4-benzodiazepin-2-thione,(S)-(2-Indolecarbonyl)amino-1,3-dihydro-5-phenyl-2H-1,4,-benzodiazepin-2-one,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-propenamide,3-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-amino-4-chlorobenzamide,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,5-(2-Fluorophenyl)-2,3-dihydro-3-((1H-indol-2-ylcarbonyl)amino)-2-oxo-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,4-Bromo-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide,N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)-benzamide,(S)-N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)benzamide,N-(2-Chlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,N-(2,4-Dichlorophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-nitrophenyl)-urea,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-chlorophenyl)-urea3-N-(2,3-Dihydro-9-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,3-N-(2,3-Dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,3-N-(2,3-Dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-urea,3-N-(2,3-Dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,N-(3-Methoxyphenyl)-N'-(2,3-dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,8. A compound of claim 6 whichis:3-((((4-Chlorophenyl)amino)carbonyl)amino)-5-2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,3-((((4-Chlorophenyl)amino)carbonyl)amino)-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,1-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)-acetyl)pyrrolidine,1-((3-((((4-Chlorophenyl)amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)-4-methylpiperazine,3-(((4-Chlorophenyl)acetyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-aceticacid ethyl ester,N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-phenylurea,N-(4-Nitrophenyl)-N'-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)N'-(3-methoxyphenyl)-urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-bromophenyl)-urea,1-{[3-[(((3-Methoxyphenyl)amino)carbonyl)amino]-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl]acetyl}pyrrolidine,3-{[((3-Methoxyphenyl)amino)carbonyl)amino]-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,3-{[((2-Chlorophenyl)amino)carbonyl]amino}-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-chlorophenyl)-urea.9. A compound whichis3-N-(2,3-Dihydro-1-methyl-2-oxo-5-(p-tolyl)-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,3-N-(2,3-Dihydro-1,9-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,3-N-(2,3-Dihydro-1,8-dimethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-phenyl-2-propenamide,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(2-chlorophenyl)-urea,(S)-N-(5-(2-Fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-4-(trifluoromethyl)benzamide,3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(2-indolecarbonylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,3(S)-(+)-1,3-Dihydro-5-(2-fluorophenyl)-3-(3-iodobenzoylamino)-1-methyl-2H-1,4-benzodiazepin-2-one,3(S)-(-)-1,3-Dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,3-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-amino-4-chlorobenzamide,4-Bromo-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide,1,3-Dihydro-5-(2-fluorophenyl)-1-methyl-3(RS)-[2'-(1'-methylindole)carbonylamino]-2H-1,4-benzodiazepin-2-one,(S)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl)-urea,1,3-dihydro-1-methyl-3(RS)-[2-(1-methylindole)carbonylamino]-5-phenyl-2H-1,4-benzodiazepin-2-one,1-Carboxymethyl-1,3-dihydro-3(RS)-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one,or3(S)-(+)-1,3-Dihydro-3-(4-chlorobenzoylamino)-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepin-2-one,or a pharmaceutically acceptable salt thereof.
 10. A compound whichis3-{[((3-Methoxyphenyl)amino)carbonyl)amino]-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,1-((3-((((4-Chlorophenyl)amino)carbonyl)amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)acetyl)pyrrolidine,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)-urea,3-{[((2-Chlorophenyl)amino)carbonyl]amino}-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetamide,(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-bromophenyl)-urea,or(R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(4-methylphenyl)-urea,orpharmaceutically acceptable salt thereof.
 11. A compound of claim 1which is3(S)-(-)-1,3-dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,or(R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea,or pharmaceutically acceptable salt thereof.
 12. The compound3(S)-(-)-1,3-dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, or pharmaceuticallyacceptable salt thereof.
 13. The compound(R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea,or pharmaceutically acceptable salt thereof.